Penicillaminamide derivatives

ABSTRACT

Compounds represented by the general formula (I) wherein n represents 1 or 2; R 1  represents, for example, a C 1 -C 10  alkyl group which may be substituted with a C 3 -C 10  cycloalkyl group or carboxyl group; R 2  represents hydrogen atom, a C 1 -C 10  alkyl group or other; and R 3  represents amino group or amidino group, whose example include trans-4-amino-[(S)-N-[(S)-2-propoxycarbonylamino-3-isopropylthio-3-methyl-butanoyl]prolyl]aminomethylcyclohexane. The compounds have potent inhibitory activity against thrombin, and are useful as anticoagulants.

This application is a 371 of PCT/JP96/02027 filed Jul. 19, 1996.

TECHNICAL FIELD

The present invention relates to novel penicillaminamide derivatives. More specifically, the present invention relates to penicillaminamide derivatives and salts thereof which have inhibitory activity against proteases, in particular, antithrombotic activity. The present invention also relates to protease inhibitors comprising said substances as active ingredients.

BACKGROUND ART

It is well known that various kinds of proteases exist in living bodies. For example, the existence of a class of serine proteases such as thrombin, factor Xa, factor IXa, factor VIIa, trypsin, plasmin, tissue plasminogen activator, kallikrein, C1 enzyme in complement, C3/C5 convertase, and tryptase are known. It is also known that various kinds of diseases are caused when these proteases are abnormally activated by. Accordingly, substances having inhibitory activity against these proteases are expected to be useful as medicaments.

For example, it is known that antithrombotic agents are effective as therapeutic medicaments for thrombosis, and for this reason, developments of protease inhibitors having antithrombotic activity have been progressing. However, these inhibitors have several problems of, for example, insufficient stability in vivo or non-selectivity to serine proteases other than thrombin, or decrease of antithrombotic activity when administered orally. Therefore, the inhibitors are not satisfactory for practical applications.

Some tripeptide derivatives containing a moiety of arginine derivative are also known as protease inhibitors. For example, D-phenylalanyl-L-prolyl-L-arginal is known as a thrombin inhibitor (for example, Folia Haematol. 109, 22 (1982)). However, this compound is relatively unstable in a living body (J. Med. Chem., 33, 1729 (1990)). There are also several reports about arginal derivatives (Japanese Patent Unexamined Publication No. (Hei)4-89498/1992; and WO 9315756), amidinophenyl-alanine derivatives (Thromb. Res., 17, 425 (1980)), arginine ketoamide derivatives (WO 9408941), boron compound derivatives (For example, J. Biol. Chem., 265, 18289 (1990), Japanese Patent Unexamined Publication Nos. Hei 4-330094/1992 and (Hei)6-298795/1994, and WO 9425049). However, the derivatives have a problem in that they have low enzymatic selectivity among serine proteases belonging to thrombin homologue, in particular, trypsin. Guanidine derivatives (Japanese Patent Unexamined Publication No. (Hei)6-25195/1994) and tetrasubstituted cyclohexylamine derivatives (WO 9425051) were reported as thrombin-specific inhibitors, however, their efficacy cannot be expected by oral administration.

Under the above-described circumstances, the inventor of the present invention conducted various research to find substances which have practically satisfactory enzyme selectivity, oral availability, and stability in vivo, and are structurally novel. As a result, they found that the penicillaminamide derivatives set forth below have desired properties, and thus achieved the present invention.

The present invention provides penicillaminamide derivatives represented by the following general formula (I) and salts thereof, and hydrates thereof and solvates thereof:

wherein:

n represents 1 or 2;

R¹ represents a C₁-C₁₀ alkyl group which may be substituted with a C₃-C₁₀ cycloalkyl group or carboxyl group, a C₆-C₁₀ aryl group which may be substituted, a C₃-C₁₀ cycloalkyl group which may be substituted, or a C₇-C₁₂aralkyl group which may be substituted;

R² represents hydrogen atom, a C₁C₁₀ alkyl group, a C₇-C₁₂ aralkyl group which may be substituted, —COR⁴ (wherein R⁴ represents hydrogen atom, a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group, a C₆-C₁₀ aryl group which may be substituted, a C₆-C₁₀ aryloxy group which may be substituted, a C₃-C₁₀ cycloalkyl group which may be substituted, a C₃-C₁₀ cycloalkyloxy group which may be substituted, a C₇-C₁₂ aralkyl group which may be substituted, or a C₇-C₁₂ aralkyloxy group), or —SO₂R⁵ (wherein R⁵ represents a C₁-C₁ alkyl group, a C₆-C₁₀ aryl group which may be substituted, a C₃-C₁₀ cycloalkyl group which may be substituted, or a C₇-C₁₂ aralkyl group which may be substituted), and

R³ represents amino group or amidino group, provided that the compounds wherein:

R¹ represents methyl group, R² represents ethoxycarbonyl group, R³ represents amino group, and n represents 1;

R¹ represents methyl group, R² represents methylsulfonyl group, R³ represents amino group, and n represents 1;

R¹ represents ethyl group, R² represents methylsulfonyl group, R³ represents amino group, and n represents 1; and

R¹ represents isopropyl group, R² represents ethoxycarbonyl group, R³ represents amidino group, and n represents 1 are excluded.

According to other aspects of the present invention, there are provided medicament comprising a substance selected from the group consisting of the aforementioned penicillaminamide derivatives and salts thereof, and hydrates thereof and solvates thereof; and pharmaceutical compositions comprising a substance selected from the group consisting of the aforementioned penicillaminamide derivatives and salts thereof, and hydrates thereof and solvates thereof as an active ingredient, together with a pharmaceutically acceptable carrier. The aforementioned medicaments and pharmaceutical compositions are useful for preventive and/or therapeutic treatment of diseases caused by hyperfunction of protease activity, for example, they are useful as antithrombotic agents, i.e., orally available anticoagulant agents. Protease inhibitors comprising a substance selected from the group consisting of the aforementioned penicillaminamide derivatives and salts thereof, and hydrates thereof and solvates thereof are also provided according to further aspect of the present invention.

According to still further aspects of the present invention, there are provided a use of a substance selected from the group consisting of the aforementioned penicillaminamide derivatives and salts thereof, and hydrates thereof and solvates thereof for the manufacture of the above-described pharmaceutical compositions; and a method for therapeutic treatment of a disease caused by hyperfunction of protease activity, which comprises administering to a patient a therapeutically and/or preventively effective amount of a substance selected from the group consisting of the aforementioned penicillaminamide derivatives and salts thereof, and hydrates thereof and solvates thereof.

DETAILED DESCRIPTION

The penicillaminamide derivatives of the present invention are represented by the formula (I) mentioned above.

Examples of the C₁-C₁₀ alkyl group in the above definition include, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group, 1,1-dimethylpropyl group, neopentyl group, n-hexyl group, 1-methyl-1-ethylpropyl group, n-heptyl group, 1,1-diethylpropyl group, n-octyl group, n-nonyl group, and n-decyl group.

Examples of the C₆-C₁₀ aryl group include, for example, phenyl group, tolyl group, and naphthyl group.

Examples of the C₃-C₁₀ cycloalkyl group include, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, and cyclodecyl group. Examples of the C₁-C₁₀ alkoxy group include, for example, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy group, t-butoxy group, n-pentyloxy group, neopentyloxy group, n-hexyloxy group, n-heptyloxy group, n-octyloxy group, n-nonyloxy group, and n-decyloxy group. Examples of the C₃-C₁₀ cycloalkyloxy group include, for example, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, and cycloheptyloxy group. Examples of the C₇-C₁₂ aralkyloxy group include, for example, benzyloxy group, phenylethyloxy group, phenylpropyloxy group, and naphthylmethyloxy group, and examples of the C₆-C₁₀ aryloxy group include, for example, phenyloxy group, tolyloxy group, and naphthyloxy group.

Examples of the C₇-C₁₂ aralkyl group include, for example, benzyl group, phenylethyl group, phenylpropyl group, and naphthylmethyl group.

When the definitions of the functional groups of the aforementioned general formula refer to “which may be substituted,” examples of the substituents include, for example, a C₁-C₆ alkyl group such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, isobutyl group, t-butyl group, n-pentyl group, and n-hexyl group; a C₁-C₆ haloalkyl group such as chloromethyl group, bromomethyl group, dichloromethyl group, 1-chloroethyl group, 2-chloroethyl group, 3-chloropropyl group, 4-chlorobutyl group, 5-chloropentyl group, 6-chlorohexyl group, difluoromethyl group, and trifluoromethyl group; a C₁-C₆ alkoxy group such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, s-butoxy group, isobutyloxy group, t-butyloxy group, n-pentyloxy group, and n-hexyloxy group; hydroxyl group; carboxyl group; a C₂-C₇ carboxyalkyl group such as carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group, 5-carboxypentyl group, and 6-carboxyhexyl group; a C₂-C₇ carboxyalkyloxy group such as carboxymethoxy group, 2-carboxyethoxy group, 3-carboxypropoxy group, 4-carboxybutyloxy group, 5-carboxypentyloxy group, and 6-carboxyhexyloxy group; a C₂-C₇acyl group such as acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, and heptanoyl group; a C₂-C₇acyloxy group such as acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, pivaloyloxy group, hexanoyloxy group, and heptanoyloxy group; a C₂-C₇ alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butyloxycarbonyl group, s-butyloxycarbonyl group, isobutyloxycarbonyl group, t-butyloxycarbonyl group, n-pentyloxycarbonyl group, and n-hexyloxycarbonyl group; a C₂-C₇ alkoxycarbonyloxy group such as methoxycarbonyloxy group, ethoxycarbonyloxy group, n-propoxycarbonyloxy group, isopropoxycarbonyloxy group, n-butyloxycarbonyloxy group, s-butyloxycarbonyloxy group, isobutyloxycarbonyloxy group, t-butyloxycarbonyloxy group, n-pentyloxycarbonyloxy group, and n-hexyloxycarbonyloxy group; a C₈-C₁₀ aralkyloxycarbonyl group such as benzyloxycarbonyl group, phenylethyloxycarbonyl group, and phenylpropyloxycarbonyl group; a C₃-C₉ alkoxycarbonylalkoxy group such as methoxycarbonylmethoxy group, ethoxycarbonylmethoxy group, propoxycarbonylmethoxy group, methoxycarbonylethoxy group, ethoxycarbonylethoxy group, and propoxycarbonylethoxy group; a halogen atom such as fluorine atom, chlorine atom, and bromine atom.

Examples of preferred compounds of the present invention include the compounds of the general formula (I) wherein R¹ represents a C₄-C₁₀ alkyl group, a C₆-C₁₀ aryl group which may be substituted, a C₃-C₁₀ cycloalkyl group which may be substituted, or a C₇-C₁₂ aralkyl group which may be substituted, and R³ represents amidino group. The compounds wherein R³ represents amino group are also preferred.

Examples of more preferred compounds include the compounds of the general formula (I) wherein R² represents hydrogen atom, a C_(1-C) ₁₀ alkyl group, a C₇-C₁₂ aralkyl group which may be substituted, or —COR⁴ wherein R⁴ has the same meaning as defined above.

Examples of the most preferred compounds include the compounds of the general formula (I) wherein R² represents —COR⁴ in which R⁴ represents a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group, a C₆-C₁₀ aryl group which may be substituted, a C₆-C₁₀ aryloxy group which may be substituted, a C₃-C₁₀ cycloalkyl group which may be substituted, a C₃-C₁₀ cycloalkyloxy group which may be substituted, a C₇-C₁₂ aralkyl group which may be substituted, or a C₇-C₁₂ aralkyloxy group which may be substituted.

The penicillaminamide derivatives represented by the above general formula (I) may have various stereostructures. For example, in view of an asymmetric carbon atom as an asymmetric center, their absolute configuration may be either in (S) or (R) configuration. they may also exist as racemates. Optical isomers or diastereoisomers in pure forms, or any mixtures of these isomers or racemates fall within the scope of the present invention.

Examples of salts formed by the compounds of the present invention represented by the aforementioned general formula (I) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydriodide, sulfate, nitrate, and phosphate, and organic acid salts such as succinate, oxalate, fumarate, maleate, lactate, tartrate, citrate, acetate, glycolate, methanesulfonate, and toluenesulfonate. When the penicillaminamide derivatives of the general formula (I) have a free carboxyl group, they can form salts with pharmaceutically acceptable bases. Examples of the salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, and alkylammonium salts.

The penicillaminamide derivatives represented by the general formula (I) and may form hydrates, or may form solvates with methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride or the like. These substances also fall within the scope of the present invention.

Specific examples of the compounds of the present invention are shown below. In the table, Me represents methyl group, Et represents ethyl group, Ph represents phenyl group, n-Pr represents n-propyl group, i-Pr represents i-propyl group, Bu represents butyl group, n-Bu represents n-butyl group, i-Bu represents i-butyl group, s-bu represents s-butyl group, cyclo-Hex represents cyclohexyl group, 4-F-Benzyl represents 4-fluorobenzyl group, and 4-OMe-Benzyl represents 4-methoxybenzyl group.

TABLE 1 Com- pound No. n R¹ R² R³  1 1 —Me —H —NH₂  2 1 —Me —Me —NH₂  3 1 —Me —CH₂Ph —NH₂  4 1 —Me —COCH₃ —NH₂  5 1 —Me —COO-n-Pr —NH₂  6 1 —Me —COO-i-Pr —NH₂  7 1 —Me —SO₂Et —NH₂  8 1 —Et —H —NH₂  9 1 —Et —Me —NH₂ 10 1 —Et —CH₂Ph —NH₂ 11 1 —Et —COCH₃ —NH₂ 12 1 —Et —COOMe —NH₂ 13 1 —Et —COOEt —NH₂ 14 1 —Et —COO-n-Pr —NH₂ 15 1 —Et —COO-i-Pr —NH₂ 16 1 —Et —COO-n-Bu —NH₂ 17 1 —Et —COO-i-Bu —NH₂ 18 1 —Et —COO-t-Bu —NH₂ 19 1 —Et —COO-n-C₅H₁₁ —NH₂ 20 1 —Et —COOCH₂Ph —NH₂ 21 1 —Et —COO-cyclo- —NH₂ Hex 22 1 —Et —SO₂Et —NH₂ 23 1 —Et —SO₂Me —NH₂ 24 1 -n-Pr —H —NH₂ 25 1 -n-Pr —Me —NH₂ 26 1 -n-Pr —CO₂Ph —NH₂ 27 1 -n-Pr —COCH₃ —NH₂ 28 1 -n-Pr— CO-cyclo-Hex —NH₂ 29 1 -n-Pr —COPh —NH₂ 30 1 -n-Pr —COOMe —NH₂ 31 1 -n-Pr —COOEt —NH₂ 32 1 -n-Pr —COO-n-Pr —NH₂ 33 1 -n-Pr —COO-i-Pr —NH₂ 34 1 -n-Pr —COO-n-Bu —NH₂ 35 1 -n-Pr —COO-i-Bu —NH₂ 36 1 -n-Pr —COO-t-Bu —NH₂ 37 1 -n-Pr —COO-n-C₅H₁₁ —NH₂ 38 1 -n-Pr —COOCH₂Ph —NH₂ 39 1 -n-Pr —SO₂Me —NH₂ 40 1 -n-Pr —SO₂Et —NH₂ 41 1 -n-Pr —SO₂—I—Pr —NH₂ 42 1 -n-Pr —SO₂Ph —NH₂ 43 1 -i-Pr —H —NH₂ 44 1 -i-Pr —Me —NH₂ 45 1 -i-Pr —CH₂Ph —NH₂ 46 1 -i-Pr —COCH₃ —NH₂ 47 1 -i-Pr —CO-cyclo-Hex —NH₂ 48 1 -i-Pr —COPh —NH₂ 49 1 -i-Pr —COOMe —NH₂ 50 1 -i-Pr —COOEt —NH₂ 51 1 -i-Pr —COO-n-Pr —NH₂ 52 1 -i-Pr —COO-i-Pr —NH₂ 53 1 -i-Pr —COO-n-Bu —NH₂ 54 1 -i-Pr —COO-i-Bu —NH₂ 55 1 -i-Pr —COO-t-Bu —NH₂ 56 1 -i-Pr —COO-n-C₅H₁₁ —NH₂ 57 1 -i-Pr —COO-cyclo- —NH₂ Hex 58 1 -i-Pr —COOCH₂Ph —NH₂ 59 1 -i-Pr —SO₂Me —NH₂ 60 1 -i-Pr —SO₂Et —NH₂ 61 1 -i-Pr —SO₂-i-Pr —NH₂ 62 1 -i-Pr —SO₂Ph —NH₂ 63 1 cyclopropyl- —H —NH₂ 64 1 cyclopropyl- —Me —NH₂ 65 1 cyclopropyl- —CH₂Ph —NH₂ 66 1 cyclopropyl- —COCH₃ —NH₂ 67 1 cyclopropyl- —SO₂Me —NH₂ 68 1 cyclopropyl- —COOEt —NH₂ 69 1 cyclopropyl- —COO-i-Pr —NH₂ 70 1 cyclopropyl- —COOMe —NH₂ 71 1 -n-Bu —H —NH₂ 72 1 -n-Bu —Me —NH₂ 73 1 -n-Bu —CH₂Ph —NH₂ 74 1 -n-Bu —COCH₃ —NH₂ 75 1 -n-Bu —CO-cyclo-Hex —NH₂ 76 1 -n-Bu —COPh —NH₂ 77 1 -n-Bu —COOMe —NH₂ 78 1 -n-Bu —COOEt —NH₂ 79 1 -n-Bu —COO-n-Pr —NH₂ 80 1 -n-Bu —COO-i-Pr —NH₂ 81 1 -n-Bu —COO-n-Bu —NH₂ 82 1 -n-Bu —COO-i-Bu —NH₂ 83 1 -n-Bu —COO-t-Bu —NH₂ 84 1 -n-Bu —COO-n-C₅H₁₁ —NH₂ 85 1 -n-Bu —COOCH₂Ph —NH₂ 86 1 -n-Bu —SO₂Me —NH₂ 87 1 -n-Bu —SO₂Et —NH₂ 88 1 -n-Bu —SO₂-i-Pr —NH₂ 89 1 -n-Bu —SO₂Ph —NH₂ 90 1 -i-Bu —H —NH₂ 91 1 -i-Bu —Me —NH₂ 92 1 -i-Bu —CH₂Ph —NH₂ 93 1 -i-Bu —COCH₃ —NH₂ 94 1 -i-Bu —CO-cyclo-Hex —NH₂ 95 1 -i-Bu —COPh —NH₂ 96 1 -i-Bu —COOMe —NH₂ 97 1 -i-Bu —COOEt —NH₂ 98 1 -i-Bu —COO-n-Pr —NH₂ 99 1 -i-Bu —COO-i-Pr —NH₂ 100  1 -i-Bu —COO-n-Bu —NH₂ 101  1 -i-Bu —COO-i-Bu —NH₂ 102  1 -i-Bu —COO-t-Bu —NH₂ 103  1 -i-Bu —COO-n-C₅H₁₁ —NH₂ 104  1 -i-Bu —COO-cyclo- —NH₂ Hex 105  1 -i-Bu —COOCH₂Ph —NH₂ 106  1 -i-Bu —SO₂Me —NH₂ 107  1 -i-Bu —SO₂Et —NH₂ 108  1 -i-Bu —SO₂-i-Pr —NH₂ 109  1 -i-Bu —SO₂Ph —NH₂ 110  1 -s-Bu —H —NH₂ 111  1 -s-Bu —Me —NH₂ 112  1 -s-Bu —CH₂Ph —NH₂ 113  1 -s-Bu —COCH₃ —NH₂ 114  1 -s-Bu —COOMe —NH₂ 115  1 -s-Bu —COOEt —NH₂ 116  1 -s-Bu —COO-i-Pr —NH₂ 117  1 -s-Bu —SO₂Me —NH₂ 118  1 -cyclobutyl —H —NH₂ 119  1 -cyclobutyl —Me —NH₂ 120  1 -cyclobutyl —CH₂Ph —NH₂ 121  1 -cyclobutyl —COCH₃ —NH₂ 122  1 -cyclobutyl —CO-cyclo-Hex —NH₂ 123  1 -cyclobutyl —COPh —NH₂ 124  1 -cyclobutyl —COOMe —NH₂ 125  1 -cyclobutyl —COOEt —NH₂ 126  1 -cyclobutyl —COO-n-Pr —NH₂ 127  1 -cyclobutyl —COO-i-Pr —NH₂ 128  1 -cyclobutyl —COO-n-Bu —NH₂ 129  1 -cyclobutyl —COO-i-Bu —NH₂ 130  1 -cyclobutyl —COO-t-Bu —NH₂ 131  1 -cyclobutyl —COO-n-C₅H₁₁ —NH₂ 132  1 -cyclobutyl —COO-cyclo- —NH₂ Hex 133  1 -cyclobutyl —COOCH₂Ph —NH₂ 134  1 -cyclobutyl —SO₂Me —NH₂ 135  1 -cyclobutyl —SO₂Et —NH₂ 136  1 -cyclobutyl —SO₂-i-Pr —NH₂ 137  1 -cyclobutyl —SO₂Ph —NH₂ 138  1 -n-C₅H₁₁ —H —NH₂ 139  1 -n-C₅H₁₁ —Me —NH₂ 140  1 -n-C₅H₁₁ —CH₂Ph —NH₂ 141  1 -n-C₅H₁₁ —COCH₃ —NH₂ 142  1 -n-C₅H₁₁ —CO-cyclo-Hex —NH₂ 143  1 -n-C₅H₁₁ —COPh —NH₂ 144  1 -n-C₅H₁₁ —COOMe —NH₂ 145  1 -n-C₅H₁₁ —COOEt —NH₂ 146  1 -n-C₅H₁₁ —COO-n-Pr —NH₂ 147  1 -n-C₅H₁₁ —COO-i-Pr —NH₂ 148  1 -n-C₅H₁₁ —COO-n-Bu —NH₂ 149  1 -n-C₅H₁₁ —COO-i-Bu —NH₂ 150  1 -n-C₅H₁₁ —COO-t-Bu —NH₂ 151  1 -n-C₅H₁₁ —COO-n-C₅H₁₁ —NH₂ 152  1 -n-C₅H₁₁ —COOCH₂Ph —NH₂ 153  1 -n-C₅H₁₁ —SO₂Me —NH₂ 154  1 -n-C₅H₁₁ —SO₂Et —NH₂ 155  1 -n-C₅H₁₁ —SO₂-i-Pr —NH₂ 156  1 -n-C₅H₁₁ —SO₂Ph —NH₂ 157  1 -cyclopentyl —H —NH₂ 158  1 -cyclopentyl —Me —NH₂ 159  1 -cyclopentyl —CH₂Ph —NH₂ 160  1 -cyclopentyl —COCH₃ —NH₂ 161  1 -cyclopentyl —CO-cyclo-Hex —NH₂ 162  1 -cyclopentyl —COPh —NH₂ 163  1 -cyclopentyl —COOMe —NH₂ 164  1 -cyclopentyl —COOEt —NH₂ 165  1 -cyclopentyl —COO-n-Pr —NH₂ 166  1 -cyclopentyl —COO-n-Bu —NH₂ 167  1 -cyclopentyl —COO-i-Bu —NH₂ 168  1 -cyclopentyl —COO-t-Bu —NH₂ 169  1 -cyclopentyl —COO-n-C₅H₁₁ —NH₂ 170  1 -cyclopentyl —SO₂Me —NH₂ 171  1 -cyclopentyl —SO₂Et —NH₂ 172  1 -cyclopentyl —SO₂-i-Pr —NH₂ 173  1 -cyclopentyl —SO₂Ph —NH₂ 174  1 —CH(CH₂CH₃)₂ —H —NH₂ 175  1 —CH(CH₂CH₃)₂ —Me —NH₂ 176  1 —CH(CH₂CH₃)₂ —CH₂Ph —NH₂ 177  1 —CH(CH₂CH₃)₂ —COCH₃ —NH₂ 178  1 —CH(CH₂CH₃)₂ —CO-cyclo-Hex —NH₂ 179  1 —CH(CH₂CH₃)₂ —COPh —NH₂ 180  1 —CH(CH₂CH₃)₂ —COOMe —NH₂ 181  1 —CH(CH₂CH₃)₂ —COOEt —NH₂ 182  1 —CH(CH₂CH₃)₂ —COO-n-Pr —NH₂ 183  1 —CH(CH₂CH₃)₂ —COO-i-Pr —NH₂ 184  1 —CH(CH₂CH₃)₂ —COO-n-Bu —NH₂ 185  1 —CH(CH₂CH₃)₂ —COO-i-Bu —NH₂ 186  1 —CH(CH₂CH₃)₂ —COO-t-Bu —NH₂ 187  1 —CH(CH₂CH₃)₂ —COO-n-C₅H₁₁ —NH₂ 188  1 —CH(CH₂CH₃)₂ —SO₂Me —NH₂ 189  1 —CH(CH₂CH₃)₂ —SO₂Et —NH₂ 190  1 —CH(CH₂CH₃)₂ —SO₂-i-Pr —NH₂ 191  1 —CH(CH₂CH₃)₂ —SO₂Ph —NH₂ 192  1 -cyclohexyl —H —NH₂ 193  1 -cyclohexyl —Me —NH₂ 194  1 -cyclohexyl —CH₂Ph —NH₂ 195  1 -cyclohexyl —COCH₃ —NH₂ 196  1 -cyclohexyl —COOMe —NH₂ 197  1 -cyclohexyl —COOEt —NH₂ 198  1 -cyclohexyl —COO-i-Pr —NH₂ 199  1 -cyclohexyl —SO₂Me —NH₂ 200  1 -cyclohexyl —SO₂-i-Pr —NH₂ 201  1 —Ph —H —NH₂ 202  1 —Ph —Me —NH₂ 203  1 —Ph —CH₂Ph —NH₂ 204  1 —Ph —COCH₃ —NH₂ 205  1 —Ph —COOMe —NH₂ 206  1 —Ph —COOEt —NH₂ 207  1 —Ph —COO-i-Pr —NH₂ 208  1 —Ph —SO₂Me —NH₂ 209  1 —Ph —SO₂-i-Pr —NH₂ 210  1 -Benzyl —H —NH₂ 211  1 -Benzyl —Me —NH₂ 212  1 -Benzyl —CH₂Ph —NH₂ 213  1 -Benzyl —COCH₃ —NH₂ 214  1 -Benzyl —COOEt —NH₂ 215  1 -Benzyl —COO-n-Pr —NH₂ 216  1 -Benzyl —COO-i-Pr —NH₂ 217  1 -Benzyl —SO₂Me —NH₂ 218  1 4-F-Benzyl- —H —NH₂ 219  1 4-F-Benzyl- —Me —NH₂ 220  1 4-F-Benzyl- —CH₂Ph —NH₂ 221  1 4-F-Benzyl- —COCH₃ —NH₂ 222  1 4-F-Benzyl- —COOMe —NH₂ 223  1 4-F-Benzyl- —COOEt —NH₂ 224  1 4-F-Benzyl- —COO-i-Pr —NH₂ 225  1 4-F-Benzyl- —SO₂Me —NH₂ 226  1 4-OMe-Benzyl- —H —NH₂ 227  1 4-OMe-Benzyl- —Me —NH₂ 228  1 4-OMe-Benzyl- —CH₂Ph —NH₂ 229  1 4-OMe-Benzyl- —COCH₃ —NH₂ 230  1 4-OMe-Benzyl- —COOMe —NH₂ 231  1 4-OMe-Benzyl- —COOEt —NH₂ 232  1 4-OMe-Benzyl- —COO-i-Pr —NH₂ 233  1 4-OMe-Benzyl- —SO₂Me —NH₂ 234  1 —CH₂-cyclo-Hex —H —NH₂ 235  1 —CH₂-cyclo-Hex —Me —NH₂ 236  1 —CH₂-cyclo-Hex —CH₂Ph —NH₂ 237  1 —CH₂-cyclo-Hex —COCH₃ —NH₂ 238  1 —CH₂-cyclo-Hex —COOMe —NH₂ 239  1 —CH₂-cyclo-Hex —COOEt —NH₂ 240  1 —CH₂-cyclo-Hex —COO-i-Pr —NH₂ 241  1 —CH₂-cyclo-Hex —COO-n-Pr —NH₂ 242  1 —CH₂-cyclo-Hex —SO₂Me —NH₂ 243  1 —CH₂C(CH₃)₃ —H —NH₂ 244  1 —CH₂C(CH₃)₃ —Me —NH₂ 245  1 —CH₂C(CH₃)₃ —CH₂Ph —NH₂ 246  1 —CH₂C(CH₃)₃ —COCH₃ —NH₂ 247  1 —CH₂C(CH₃)₃ —COOEt —NH₂ 248  1 —CH₂C(CH₃)₃ —COO-n-Pr —NH₂ 249  1 —CH₂C(CH₃)₃ —COO-i-Pr —NH₂ 250  1 —CH₂C(CH₃)₃ —SO₂Me —NH₂ 251  1 —(CH₂)₂CH(CH₃)₂ —H —NH₂ 252  1 —(CH₂)₂CH(CH₃)₂ —Me —NH₂ 253  1 —(CH₂)₂CH(CH₃)₂ —COCH₃ —NH₂ 254  1 —(CH₂)₂CH(CH₃)₂ —COOEt —NH₂ 255  1 —(CH₂)₂CH(CH₃)₂ —COO-n-Pr —NH₂ 256  1 —(CH₂)₂CH(CH₃)₂ —COO-i-Pr —NH₂ 257  1 —(CH₂)₂CH(CH₃)₂ —SO₂Me —NH₂ 258  2 —Me —H —NH₂ 259  2 —Me —Me —NH₂ 260  2 —Me —COCH₃ —NH₂ 261  2 —Me —COOMe —NH₂ 262  2 —Me —COOEt —NH₂ 263  2 —Me —COO-i-Pr —NH₂ 264  2 —Me —SO₂Me —NH₂ 265  2 —Et —H —NH₂ 266  2 —Et —Me —NH₂ 267  2 —Et —COCH₃ —NH₂ 268  2 —Et —COOMe —NH₂ 269  2 —Et —COOEt —NH₂ 270  2 —Et —COO-n-Pr —NH₂ 271  2 —Et —COO-i-Pr —NH₂ 272  2 —Et —COO-n-Bu —NH₂ 273  2 —Et —COO-i-Bu —NH₂ 274  2 —Et —COO-t-Bu —NH₂ 275  2 —Et —SO₂Me —NH₂ 276  2 -n-Pr —H —NH₂ 277  2 -n-Pr —Me —NH₂ 278  2 -n-Pr —COCH₃ —NH₂ 279  2 -n-Pr —COOMe —NH₂ 280  2 -n-Pr —COOEt —NH₂ 281  2 -n-Pr —COO-n-Pr —NH₂ 282  2 -n-Pr —COO-i-Pr —NH₂ 283  2 -n-Pr —COO-n-Bu —NH₂ 284  2 -n-Pr —COO-t-Bu —NH₂ 285  2 -n-Pr —COO-i-Bu —NH₂ 286  2 -n-Pr —SO₂Me —NH₂ 287  2 -i-Pr —H —NH₂ 288  2 -i-Pr —Me —NH₂ 289  2 -i-Pr —COCH₃ —NH₂ 290  2 -i-Pr —COOMe —NH₂ 291  2 -i-Pr —COOEt —NH₂ 292  2 -i-Pr —COO-n-Pr —NH₂ 293  2 -i-Pr —COO-i-Pr —NH₂ 294  2 -i-Pr —COO-n-Bu —NH₂ 295  2 -i-Pr —COO-i-Bu —NH₂ 296  2 -i-Pr —COO-t-Bu —NH₂ 297  2 -i-Pr —SO₂Me —NH₂ 298  2 -n-Bu —H —NH₂ 299  2 -n-Bu —Me —NH₂ 300  2 -n-Bu —COCH₃ —NH₂ 301  2 -n-Bu —COOMe —NH₂ 302  2 -n-Bu —COOEt —NH₂ 303  2 -n-Bu —COO-n-Pr —NH₂ 304  2 -n-Bu —COO-i-Pr —NH₂ 305  2 -n-Bu —COO-n-Bu —NH₂ 306  2 -n-Bu —COO-i-Bu —NH₂ 307  2 -n-Bu —COO-t-Bu —NH₂ 308  2 -n-Bu —SO₂Me —NH₂ 309  2 -i-Bu —H —NH₂ 310  2 -i-Bu —Me —NH₂ 311  2 -i-Bu —COCH₃ —NH₂ 312  2 -i-Bu —COOMe —NH₂ 313  2 -i-Bu —COOEt —NH₂ 314  2 -i-Bu —COO-n-Pr —NH₂ 315  2 -i-Bu —COO-i-Pr —NH₂ 316  2 -i-Bu —COO-n-Bu —NH₂ 317  2 -i-Bu —COO-i-Bu —NH₂ 318  2 -i-Bu —COO-t-Bu —NH₂ 319  2 -i-Bu —SO₂Me —NH₂ 320  2 -cyclobutyl —H —NH₂ 321  2 -cyclobutyl —Me —NH₂ 322  2 -cyclobutyl —COCH₃ —NH₂ 323  2 -cyclobutyl —COOMe —NH₂ 324  2 -cyclobutyl —COOEt —NH₂ 325  2 -cyclobutyl —COO-n-Pr —NH₂ 326  2 -cyclobutyl —COO-i-Pr —NH₂ 327  2 -cyclobutyl —COO-t-Bu —NH₂ 328  2 -cyclobutyl —SO₂Me —NH₂ 329  2 -cyclopentyl —H —NH₂ 330  2 -cyclopentyl —Me —NH₂ 331  2 -cyclopentyl —COCH₃ —NH₂ 332  2 -cyclopentyl —COOMe —NH₂ 333  2 -cyclopentyl —COOEt —NH₂ 334  2 -cyclopentyl —COO-n-Pr —NH₂ 335  2 -cyclopentyl —COO-i-Pr —NH₂ 336  2 -cyclopentyl —COO-t-Bu —NH₂ 337  2 -Benzyl —H —NH₂ 338  2 -Benzyl —Me —NH₂ 339  2 -Benzyl —COCH₃ —NH₂ 340  2 -Benzyl —COOMe —NH₂ 341  2 -Benzyl —COOEt —NH₂ 342  2 -Benzyl —COO-n-Pr —NH₂ 343  2 -Benzyl —COO-i-Pr —NH₂ 344  2 -Benzyl —COO-t-Bu —NH₂ 345  2 -Benzyl —SO₂Me —NH₂ 346  2 —CH₂C(CH₃)₃ —H —NH₂ 347  2 —CH₂C(CH₃)₃ —Me —NH₂ 348  2 —CH₂C(CH₃)₃ —COCH₃ —NH₂ 349  2 —CH₂C(CH₃)₃ —COOMe —NH₂ 350  2 —CH₂C(CH₃)₃ —COOEt —NH₂ 351  2 —CH₂C(CH₃)₃ —COO-n-Pr —NH₂ 352  2 —CH₂C(CH₃)₃ —COO-i-Pr —NH₂ 353  2 —CH₂C(CH₃)₃ COO-t-Bu —NH₂ 354  2 —CH₂C(CH₃)₃ —SO₂Me —NH₂ 355  2 —CH(CH₂CH₃)₂ —H —NH₂ 356  2 —CH(CH₂CH₃)₂ —Me —NH₂ 357  2 —CH(CH₂CH₃)₂ —COCH₃ —NH₂ 358  2 —CH(CH₂CH₃)₂ —COOMe —NH₂ 359  2 —CH(CH₂CH₃)₂ —COOEt —NH₂ 360  2 —CH(CH₂CH₃)₂ —COO-n-Pr —NH₂ 361  2 —CH(CH₂CH₃)₂ —COO-i-Pr —NH₂ 362  2 —CH(CH₂CH₃)₂ —COO-t-Bu —NH₂ 363  2 —CH(CH₂CH₃)₂ —SO₂Me —NH₂ 364  1 —Me —H —C(NH₂)═NH 365  1 —Me —Me —C(NH₂)═NH 366  1 —Me —CH₂Ph —C(NH₂)═NH 367  1 —Me —COCH₃ —C(NH₂)═NH 368  1 —Me —COO-n-Pr —C(NH₂)═NH 369  1 —Me —COO-i-Pr —C(NH₂)═NH 370  1 —Me —SO₂Me —C(NH₂)═NH 371  1 —Et —H —C(NH₂)═NH 372  1 —Et —Me —C(NH₂)═NH 373  1 —Et —CH₂Ph —C(NH₂)═NH 374  1 —Et —COCH₃ —C(NH₂)═NH 375  1 —Et —COOMe —C(NH₂)═NH 376  1 —Et —COOEt —C(NH₂)═NH 377  1 —Et —COO-n-Pr —C(NH₂)═NH 378  1 —Et —COO-i-Pr —C(NH₂)═NH 379  1 —Et —COO-n-Bu —C(NH₂)═NH 380  1 —Et —COO-i-Bu —C(NH₂)═NH 381  1 —Et —COO-t-Bu —C(NH₂)═NH 382  1 —Et —COO-n-C₅H₁₁ —C(NH₂)═NH 383  1 —Et —COOCH₂Ph —C(NH₂)═NH 384  1 —Et —SO₂Me —C(NH₂)═NH 385  1 —Et —SO₂Et —C(NH₂)═NH 386  1 —Et —SO₂-i-Pr —C(NH₂)═NH 387  1 -n-Pr —H —C(NH₂)═NH 388  1 -n-Pr —Me —C(NH₂)═NH 389  1 -n-Pr —CH₂Ph —C(NH₂)═NH 390  1 -n-Pr —COCH₃ —C(NH₂)═NH 391  1 -n-Pr —COPh —C(NH₂)═NH 392  1 -n-Pr —COOMe —C(NH₂)═NH 393  1 -n-Pr —COOEt —C(NH₂)═NH 394  1 -n-Pr —COO-n-Pr —C(NH₂)═NH 395  1 -n-Pr —COO-i-Pr —C(NH₂)═NH 396  1 -n-Pr —COO-n-Bu —C(NH₂)═NH 397  1 -n-Pr —COO-i-Bu —C(NH₂)═NH 398  1 -n-Pr —COO-t-Bu —C(NH₂)═NH 399  1 -n-Pr —COO-n-C₅H₁₁ —C(NH₂)═NH 400  1 -n-Pr —COOCH₂Ph —C(NH₂)═NH 401  1 -n-Pr —SO₂Me —C(NH₂)═NH 402  1 -n-Pr —SO₂Et —C(NH₂)═NH 403  1 -n-Pr —SO₂-i-Pr —C(NH₂)═NH 404  1 -n-Pr —SO₂Ph —C(NH₂)═NH 405  1 -i-Pr —H —C(NH₂)═NH 406  1 -i-Pr —Me —C(NH₂)═NH 407  1 -i-Pr —CH₂Ph —C(NH₂)═NH 408  1 -i-Pr —COCH₃ —C(NH₂)═NH 409  1 -i-Pr —COPh —C(NH₂)═NH 410  1 -i-Pr —COO-n-Pr —C(NH₂)═NH 411  1 -i-Pr —COO-i-Pr —C(NH₂)═NH 412  1 -i-Pr —COO-n-Bu —C(NH₂)═NH 413  1 -i-Pr —COO-i-Bu —C(NH₂)═NH 414  1 -i-Pr —COO-t-Bu —C(NH₂)═NH 415  1 -i-Pr —COO-n-C₅H₁₁ —C(NH₂)═NH 416  1 -i-Pr —COOCH₂Ph —C(NH₂)═NH 417  1 -i-Pr —SO₂Me —C(NH₂)═NH 418  1 -i-Pr —SO₂Et —C(NH₂)═NH 419  1 -i-Pr —COOMe —C(NH₂)═NH 420  1 -i-Pr —SO₂Ph —C(NH₂)═NH 421  1 cyclopropyl- —H —C(NH₂)═NH 422  1 cyclopropyl- —Me —C(NH₂)═NH 423  1 cyclopropyl- —COCH₃ —C(NH₂)═NH 424  1 cyclopropyl- —SO₂Me —C(NH₂)═NH 425  1 cyclopropyl- —COOEt —C(NH₂)═NH 426  1 cyclopropyl- —COOMe —C(NH₂)═NH 427  1 cyclopropyl- —COO-i-Pr —C(NH₂)═NH 428  1 -n-Bu —H —C(NH₂)═NH 429  1 -n-Bu —Me —C(NH₂)═NH 430  1 -n-Bu —CH₂Ph —C(NH₂)═NH 431  1 -n-Bu —COCH₃ —C(NH₂)═NH 432  1 -n-Bu —COPh —C(NH₂)═NH 433  1 -n-Bu —COOMe —C(NH₂)═NH 434  1 -n-Bu —COOEt —C(NH₂)═NH 435  1 -n-Bu —COO-n-Pr —C(NH₂)═NH 436  1 -n-Bu —COO-i-Pr —C(NH₂)═NH 437  1 -n-Bu —COO-n-Bu —C(NH₂)═NH 438  1 -n-Bu —COO-i-Bu —C(NH₂)═NH 439  1 -n-Bu —COO-t-Bu —C(NH₂)═NH 440  1 -n-Bu —COO-n-C₅H₁₁ —C(NH₂)═NH 441  1 -n-Bu —COOCH₂Ph —C(NH₂)═NH 442  1 -n-Bu —SO₂Me —C(NH₂)═NH 443  1 -n-Bu —SO₂Et —C(NH₂)═NH 444  1 -n-Bu —SO₂-i-Pr —C(NH₂)═NH 445  1 -n-Bu —SO₂Ph —C(NH₂)═NH 446  1 -i-Bu —H —C(NH₂)═NH 447  1 -i-Bu —Me —C(NH₂)═NH 448  1 -i-Bu —CH₂Ph —C(NH₂)═NH 449  1 -i-Bu —COCH₃ —C(NH₂)═NH 450  1 -i-Bu —COPh —C(NH₂)═NH 451  1 -i-Bu —COOMe —C(NH₂)═NH 452  1 -i-Bu —COOEt —C(NH₂)═NH 453  1 -i-Bu —COO-n-Pr —C(NH₂)═NH 454  1 -i-Bu —COO-i-Pr —C(NH₂)═NH 455  1 -i-Bu —COO-n-Bu —C(NH₂)═NH 456  1 -i-Bu —COO-i-Bu —C(NH₂)═NH 457  1 -i-Bu —COO-t-Bu —C(NH₂)═NH 458  1 -i-Bu —COO-n-C₅H₁₁ —C(NH₂)═NH 459  1 -i-Bu —COOCH₂Ph —C(NH₂)═NH 460  1 -i-Bu —SO₂Me —C(NH₂)═NH 461  1 -i-Bu —SO₂Et —C(NH₂)═NH 462  1 -i-Bu —SO₂-i-Pr —C(NH₂)═NH 463  1 -i-Bu —SO₂Ph —C(NH₂)═NH 464  1 -cyclobutyl —H —C(NH₂)═NH 465  1 -cyclobutyl —Me —C(NH₂)═NH 466  1 -cyclobutyl —COCH₃ —C(NH₂)═NH 467  1 -cyclobutyl —COOMe —C(NH₂)═NH 468  1 -cyclobutyl —COOEt —C(NH₂)═NH 469  1 -cyclobutyl —COO-n-Pr —C(NH₂)═NH 470  1 -cyclobutyl —COO-i-Pr —C(NH₂)═NH 471  1 -cyclobutyl —COO-n-Bu —C(NH₂)═NH 472  1 -cyclobutyl —COO-i-Bu —C(NH₂)═NH 473  1 -cyclobutyl —COO-t-Bu —C(NH₂)═NH 474  1 -cyclobutyl —COO-n-C₅H₁₁ —C(NH₂)═NH 475  1 -cyclobutyl —COOCH₂Ph —C(NH₂)═NH 476  1 -cyclobutyl —SO₂Me —C(NH₂)═NH 477  1 -cyclobutyl —SO₂-i-Pr —C(NH₂)═NH 478  1 -cyclobutyl —SO₂Ph —C(NH₂)═NH 479  1 -n-C₅H₁₁ —H —C(NH₂)═NH 480  1 -n-C₅H₁₁ —Me —C(NH₂)═NH 481  1 -n-C₅H₁₁ —COCH₃ —C(NH₂)═NH 482  1 -n-C₅H₁₁ —COOMe —C(NH₂)═NH 483  1 -n-C₅H₁₁ —COOEt —C(NH₂)═NH 484  1 -n-C₅H₁₁ —COO-n-Pr —C(NH₂)═NH 485  1 -n-C₅H₁₁ —COO-i-Pr —C(NH₂)═NH 486  1 -n-C₅H₁₁ —COO-n-Bu —C(NH₂)═NH 487  1 -n-C₅H₁₁ —COO-i-Bu —C(NH₂)═NH 488  1 -n-C₅H₁₁ —COO-t-Bu —C(NH₂)═NH 489  1 -n-C₅H₁₁ —COO-n-C₅H₁₁ —C(NH₂)═NH 490  1 -n-C₅H₁₁ —COOCH₂Ph —C(NH₂)═NH 491  1 -n-C₅H₁₁ —SO₂Me —C(NH₂)═NH 492  1 -n-C₅H₁₁ —SO₂Et —C(NH₂)═NH 493  1 -n-C₅H₁₁ —SO₂-i-Pr —C(NH₂)═NH 494  1 -n-C₅H₁₁ —SO₂Ph —C(NH₂)═NH 495  1 -cyclopentyl —H —C(NH₂)═NH 496  1 -cyclopentyl —Me —C(NH₂)═NH 497  1 -cyclopentyl —COCH₃ —C(NH₂)═NH 498  1 -cyclopentyl —COOMe —C(NH₂)═NH 499  1 -cyclopentyl —COOEt —C(NH₂)═NH 500  1 -cyclopentyl —COO-n-Pr —C(NH₂)═NH 501  1 -cyclopentyl —COO-i-Pr —C(NH₂)═NH 502  1 -cyclopentyl —COO-n-Bu —C(NH₂)═NH 503  1 -cyclopentyl —COO-i-Bu —C(NH₂)═NH 504  1 -cyclopentyl —COO-t-Bu —C(NH₂)═NH 505  1 -cyclopentyl —COO-n-C₅H₁₁ —C(NH₂)═NH 506  1 -cyclopentyl —SO₂Me —C(NH₂)═NH 507  1 -cyclopentyl —SO₂Et —C(NH₂)═NH 508  1 -cyclopentyl —SO₂-i-Pr —C(NH₂)═NH 509  1 -cyclopentyl —SO₂Ph —C(NH₂)═NH 510  1 —CH(CH₂CH₃)₂ —H —C(NH₂)═NH 511  1 —CH(CH₂CH₃)₂ —Me —C(NH₂)═NH 512  1 —CH(CH₂CH₃)₂ —COCH₃ —C(NH₂)═NH 513  1 —CH(CH₂CH₃)₂ —COOMe —C(NH₂)═NH 514  1 —CH(CH₂CH₃)₂ —COOEt —C(NH₂)═NH 515  1 —CH(CH₂CH₃)₂ —COO-n-Pr —C(NH₂)═NH 516  1 —CH(CH₂CH₃)₂ —COO-i-Pr —C(NH₂)═NH 517  1 —CH(CH₂CH₃)₂ —COO-n-Bu —C(NH₂)═NH 518  1 —CH(CH₂CH₃)₂ —COO-i-Bu —C(NH₂)═NH 519  1 —CH(CH₂CH₃)₂ —COO-t-Bu —C(NH₂)═NH 520  1 —CH(CH₂CH₃)₂ —COO-n-C₅H₁₁ —C(NH₂)═NH 521  1 —CH(CH₂CH₃)₂ —SO₂Me —C(NH₂)═NH 522  1 —CH(CH₂CH₃)₂ —SO₂Et —C(NH₂)═NH 523  1 —CH(CH₂CH₃)₂ —SO₂-i-Pr —C(NH₂)═NH 524  1 —CH(CH₂CH₃)₂ —SO₂Ph —C(NH₂)═NH 525  1 -Benzyl —H —C(NH₂)═NH 526  1 -Benzyl —Me —C(NH₂)═NH 527  1 -Benzyl —COCH₃ —C(NH₂)═NH 528  1 -Benzyl —COOMe —C(NH₂)═NH 529  1 -Benzyl —COOEt —C(NH₂)═NH 530  1 -Benzyl —COO-n-Pr —C(NH₂)═NH 531  1 -Benzyl —COO-i-Pr —C(NH₂)═NH 532  1 -Benzyl —COO-n-Bu —C(NH₂)═NH 533  1 -Benzyl —SO₂Me —C(NH₂)═NH 534  1 4-F-Benzyl- —H —C(NH₂)═NH 535  1 4-F-Benzyl- —Me —C(NH₂)═NH 536  1 4-F-Benzyl- —COCH₃ —C(NH₂)═NH 537  1 4-F-Benzyl- —COOEt —C(NH₂)═NH 538  1 4-F-Benzyl- —COO-n-Pr —C(NH₂)═NH 539  1 4-F-Benzyl- —COO-i-Pr —C(NH₂)═NH 540  1 4-F-Benzyl- —COO-n-Bu —C(NH₂)═NH 541  1 4-F-Benzyl- —SO₂Me —C(NH₂)═NH 542  1 4-OMe-Benzyl- —H —C(NH₂)═NH 543  1 4-OMe-Benzyl- —Me —C(NH₂)═NH 544  1 4-OMe-Benzyl- —COCH₃ —C(NH₂)═NH 545  1 4-OMe-Benzyl- —COOEt —C(NH₂)═NH 546  1 4-OMe-Benzyl- —COO-n-Pr —C(NH₂)═NH 547  1 4-OMe-Benzyl- —COO-i-Pr —C(NH₂)═NH 548  1 4-OMe-Benzyl- —COO-n-Bu —C(NH₂)═NH 549  1 4-OMe-Benzyl- —SO₂Me —C(NH₂)═NH 550  1 —CH₂-cyclo-Hex —H —C(NH₂)═NH 551  1 —CH₂-cyclo-Hex —Me —C(NH₂)═NH 552  1 —CH₂-cyclo-Hex —COCH₃ —C(NH₂)═NH 553  1 —CH₂-cyclo-Hex —COOEt —C(NH₂)═NH 554  1 —CH₂-cyclo-Hex —COO-n-Pr —C(NH₂)═NH 555  1 —CH₂-cyclo-Hex —COO-i-Pr —C(NH₂)═NH 556  1 —CH₂-cyclo-Hex —COO-n-Bu —C(NH₂)═NH 557  1 —CH₂-cyclo-Hex —COO-i-Bu —C(NH₂)═NH 558  1 —CH₂-cyclo-Hex —SO₂Me —C(NH₂)═NH 559  1 —CH₂C(CH₃)₃ —H —C(NH₂)═NH 560  1 —CH₂C(CH₃)₃ —Me —C(NH₂)═NH 561  1 —CH₂C(CH₃)₃ —COCH₃ —C(NH₂)═NH 562  1 —CH₂C(CH₃)₃ —COOEt —C(NH₂)═NH 563  1 —CH₂C(CH₃)₃ —COO-n-Pr —C(NH₂)═NH 564  1 —CH₂C(CH₃)₃ —COO-i-Pr —C(NH₂)═NH 565  1 —CH₂C(CH₃)₃ —COO-n-Bu —C(NH₂)═NH 566  1 —CH₂C(CH₃)₃ —COO-i-Bu —C(NH₂)═NH 567  1 —CH₂C(CH₃)₃ —SO₂Me —C(NH₂)═NH 568  1 —(CH₂)₂CH(CH₃)₂ —H —C(NH₂)═NH 569  1 —(CH₂)₂CH(CH₃)₂ —Me —C(NH₂)═NH 570  1 —(CH₂)₂CH(CH₃)₂ —COCH₃ —C(NH₂)═NH 571  1 —(CH₂)₂CH(CH₃)₂ —COOEt —C(NH₂)═NH 572  1 —(CH₂)₂CH(CH₃)₂ —COO-n-Pr —C(NH₂)═NH 573  1 —(CH₂)₂CH(CH₃)₂ —COO-i-Pr —C(NH₂)═NH 574  1 —(CH₂)₂CH(CH₃)₂ —COO-n-Bu —C(NH₂)═NH 575  1 —(CH₂)₂CH(CH₃)₂ —COO-i-Bu —C(NH₂)═NH 576  1 —(CH₂)₂CH(CH₃)₂ —SO₂Me —C(NH₂)═NH 577  2 —Me —H —C(NH₂)═NH 578  2 —Me —Me —C(NH₂)═NH 579  2 —Me —COCH₃ —C(NH₂)═NH 580  2 —Me —COOEt —C(NH₂)═NH 581  2 —Me —COO-n-Pr —C(NH₂)═NH 582  2 —Me —COO-i-Pr —C(NH₂)═NH 583  2 —Me —COO-n-Bu —C(NH₂)═NH 584  2 —Me —COO-i-Bu —C(NH₂)═NH 585  2 —Me —SO₂Me —C(NH₂)═NH 586  2 —Et —H —C(NH₂)═NH 587  2 —Et —Me —C(NH₂)═NH 588  2 —Et —COCH₃ —C(NH₂)═NH 589  2 —Et —COOEt —C(NH₂)═NH 590  2 —Et —COO-n-Pr —C(NH₂)═NH 591  2 —Et —COO-i-Pr —C(NH₂)═NH 592  2 —Et —COO-n-Bu —C(NH₂)═NH 593  2 —Et —COO-i-Bu —C(NH₂)═NH 594  2 —Et —SO₂Me —C(NH₂)═NH 595  2 -n-Pr —H —C(NH₂)═NH 596  2 -n-Pr —Me —C(NH₂)═NH 597  2 -n-Pr —COCH₃ —C(NH₂)═NH 598  2 -n-Pr —COOEt —C(NH₂)═NH 599  2 -n-Pr —COO-n-Pr —C(NH₂)═NH 600  2 -n-Pr —COO-i-Pr —C(NH₂)═NH 601  2 -n-Pr —COO-n-Bu —C(NH₂)═NH 602  2 -n-Pr —COO-i-Bu —C(NH₂)═NH 603  2 -n-Pr —SO₂Me —C(NH₂)═NH 604  2 -i-Pr —H —C(NH₂)═NH 605  2 -i-Pr —Me —C(NH₂)═NH 606  2 -i-Pr —COCH₃ —C(NH₂)═NH 607  2 -i-Pr —COOEt —C(NH₂)═NH 608  2 -i-Pr —COO-n-Pr —C(NH₂)═NH 609  2 -i-Pr —COO-i-Pr —C(NH₂)═NH 610  2 -i-Pr —COO-n-Bu —C(NH₂)═NH 611  2 -i-Pr —COO-i-Bu —C(NH₂)═NH 612  2 -i-Pr —SO₂Me —C(NH₂)═NH 613  2 -n-Bu —H —C(NH₂)═NH 614  2 -n-Bu —Me —C(NH₂)═NH 615  2 -n-Bu —COCH₃ —C(NH₂)═NH 616  2 -n-Bu —COOEt —C(NH₂)═NH 617  2 -n-Bu —COO-n-Pr —C(NH₂)═NH 618  2 -n-Bu —COO-i-Pr —C(NH₂)═NH 619  2 -n-Bu —COO-n-Bu —C(NH₂)═NH 620  2 -n-Bu —COO-i-Bu —C(NH₂)═NH 621  2 -n-Bu —SO₂Me —C(NH₂)═NH 622  2 -i-Bu —H —C(NH₂)═NH 623  2 -i-Bu —Me —C(NH₂)═NH 624  2 -i-Bu —COCH₃ —C(NH₂)═NH 625  2 -i-Bu —COOEt —C(NH₂)═NH 626  2 -i-Bu —COO-n-Pr —C(NH₂)═NH 627  2 -i-Bu —COO-i-Pr —C(NH₂)═NH 628  2 -i-Bu —COO-n-Bu —C(NH₂)═NH 629  2 -i-Bu —COO-i-Bu —C(NH₂)═NH 630  2 -i-Bu —SO₂Me —C(NH₂)═NH 631  2 -cyclobutyl —H —C(NH₂)═NH 632  2 -cyclobutyl —Me —C(NH₂)═NH 633  2 -cyclobutyl —COCH₃ —C(NH₂)═NH 634  2 -cyclobutyl —COOEt —C(NH₂)═NH 635  2 -cyclobutyl —COO-n-Pr —C(NH₂)═NH 636  2 -cyclobutyl —COO-i-Pr —C(NH₂)═NH 637  2 -cyclobutyl —COO-n-Bu —C(NH₂)═NH 638  2 -cyclobutyl —COO-i-Bu —C(NH₂)═NH 639  2 -cyclobutyl —SO₂Me —C(NH₂)═NH 640  2 -cyclopentyl —H —C(NH₂)═NH 641  2 -cyclopentyl —Me —C(NH₂)═NH 642  2 -cyclopentyl —COCH₃ —C(NH₂)═NH 643  2 -cyclopentyl —COOEt —C(NH₂)═NH 644  2 -cyclopentyl —COO-n-Pr —C(NH₂)═NH 645  2 -cyclopentyl —COO-i-Pr —C(NH₂)═NH 646  2 -cyclopentyl —COO-n-Bu —C(NH₂)═NH 647  2 -cyclopentyl —COO-i-Bu —C(NH₂)═NH 648  2 -cyclopentyl —SO₂Me —C(NH₂)═NH 649  2 -Benzyl —H —C(NH₂)═NH 650  2 -Benzyl —Me —C(NH₂)═NH 651  2 -Benzyl —COCH₃ —C(NH₂)═NH 652  2 -Benzyl —COOEt —C(NH₂)═NH 653  2 -Benzyl —COO-n-Pr —C(NH₂)═NH 654  2 -Benzyl —COO-i-Pr —C(NH₂)═NH 655  2 -Benzyl —COO-n-Bu —C(NH₂)═NH 656  2 -Benzyl —COO-i-Bu —C(NH₂)═NH 657  2 -Benzyl —SO₂Me —C(NH₂)═NH 658  2 -i-Pr —H —C(NH₂)═NH 659  2 -i-Pr —Me —C(NH₂)═NH 660  2 -i-Pr —COCH₃ —C(NH₂)═NH 661  2 -i-Pr —COOEt —C(NH₂)═NH 662  2 -i-Pr —COO-n-Pr —C(NH₂)═NH 663  2 -i-Pr —COO-i-Pr —C(NH₂)═NH 664  2 -i-Pr —COO-n-Bu —C(NH₂)═NH 665  2 -i-Pr —COO-i-Bu —C(NH₂)═NH 666  2 -i-Pr —SO₂Me —C(NH₂)═NH 667  2 —CH(CH₂CH₃)₂ —H —C(NH₂)═NH 668  2 —CH(CH₂CH₃)₂ —Me —C(NH₂)═NH 669  2 —CH(CH₂CH₃)₂ —COCH₃ —C(NH₂)═NH 670  2 —CH(CH₂CH₃)₂ —COOEt —C(NH₂)═NH 671  2 —CH(CH₂CH₃)₂ —COO-n-Pr —C(NH₂)═NH 672  2 —CH(CH₂CH₃)₂ —COO-i-Pr —C(NH₂)═NH 673  2 —CH(CH₂CH₃)₂ —COO-n-Bu —C(NH₂)═NH 674  2 —CH(CH₂CH₃)₂ —COO-i-Bu —C(NH₂)═NH 675  2 —CH(CH₂CH₃)₂ —SO₂Me —C(NH₂)═NH

The methods for the preparation of the compounds of the present invention will be explained below.

Compounds of the present invention can be prepared by combinations of reactions suitable to obtain the respective desired compounds. Typical reaction schemes are exemplified below, however, the methods are not limited to those described below.

In the above schemes, R¹, R² and n have the same meanings as those defined above, and P and Q represent a protective group for amino group such as benzyloxycarbonyl group and t-butyloxycarbonyl group.

In the above schemes, a known method for amide synthesis may be used for the preparations of the compounds of formulas (IV), (VII), (IX), and (XI). Examples of applicable methods include, for example, methods using a dehydration-condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3-(dimethylaminopropyl)carbodiimide, and carbonyldiimidazole, the azide methods, the acid halide methods, the acid anhydride methods, the activated ester methods and the like (see, for example, “Jikken Kagaku Koza,” 4th edition, Vol. 22, Organic Syntheses IV, p.259- (1992), Ed. by the Chemical Society of Japan, Maruzen). The reactions may be performed in an inert solvent such as tetrahydrofuran, diethyl ether, and dichloromethane under cooling, at room temperature, or with heating in a conventional manner. In the above reaction schemes, the compounds of formula (V), the compounds of formula (I) in Reaction Scheme 1, and the compounds of formula (X) can be synthesized by carrying out a deprotection reaction according to a method known in the field of peptide chemistry (see, for example, Nobuo, Izumiya et al., “Fundamentals and Experiments of Peptide Syntheses,” Maruzen).

The compound of formula (I) in Reaction Scheme 2 may be prepared by subjecting an imidate compound, obtained by treating the compound of formula (XI) with an alcohol and an inorganic acid such as hydrochloric acid, to reaction with ammonia or ammonium salt, or alternatively, by subjecting a thioamide compound, obtained by treating the compound of formula (XI) with hydrogen disulfide in the presence of an organic base such as triethylamine or pyridine, to reaction with a lower alkyl halide compound such as methyl iodide, and then reacting the resulting thioimidate compound with ammonia or ammonium salt.

Each of the compounds obtained as described above can be isolated and purified by conventional chemical techniques such as, for example, extraction, crystallization, recrystallization, or various chromatographic processes.

When the compounds of the present invention are used as medicaments, the compound, per se, may be used. Generally, however, it is preferable that the compound is used in the form of a pharmaceutical composition comprising the compound of the present invention as an active ingredient together with a pharmaceutically acceptable additive. A ratio of the active ingredient to the pharmaceutically acceptable additive may vary in the range of, for example, from 1 to 90% by weight. As pharmaceutical compositions comprising the compound of the present invention, for example, compositions for oral administration such as granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions, and liquid drugs may be administered, or alternatively, injections can be administered intravenously, intramuscularly, or subcutaneously. The compositions can be used also as suppositories. The compositions can also be provided as powders for injection and used as injections prepared upon use.

As the pharmaceutically acceptable additives, solid or liquid, and organic or inorganic carriers and diluents for pharmaceutical preparations suitable for oral, enteral, or parenteral administration may be used. As excipients used for the preparation of solid pharmaceutical compositions, for example, lactose, saccharose, starch, talc, cellulose, dextrin, china clay, calcium carbonate and the like may be used. Liquid compositions for oral administration such as emulsions, syrups, suspensions, or solutions may contain conventionally-used inert diluents such as water or vegetable oils. These liquid compositions may contain, in addition to the inert diluents, for example, auxiliaries such as moistening agents, suspending aids, sweeteners, aromatics, colorants and preservatives. Liquid compositions thus prepared may be encapsulated into capsules made of an absorbable material such as gelatin. Examples of solvents or suspension mediums used for preparation of the pharmaceutical compositions for parenteral administration such as injections, suppositories and the like include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, and lecithin. Base materials used for suppositories include, for example, cacao butter, emulsified cacao butter, lauric lipid, and Witepsol. Those pharmaceutical compositions can be manufactured by conventional methods.

Clinical dose for oral administration may generally be 0.01-1000 mg, preferably 10-1000 mg per day for an adult as a weight of the compound of the present invention. However, it is further preferable that the dose may be appropriately increased or decreased depending on age, conditions, and symptoms of a patient. The daily dose of the medicament of the present invention can be administered once a day, or alternatively, two or three times a day with appropriate intervals as divided portions. The dose may be administered intermittently.

When the medicaments are administered as injections, it is desirable that a single dose of 0.001-100 mg for an adult as a weight of the compound of the present invention is administered continuously or intermittently.

EXAMPLES

The present invention will be explained more specifically by referring to the following examples. However, the scope of the present invention is not limited to the following examples.

In the examples below, the following ordinary abbreviations are used: THF: tetrahydrofuran; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; CDI: carbonyldiimidazole; DPPA: diphenylphosphoryl azide; Z: benzyloxycarbonyl; and Boc: tertiary-butyloxycarbonyl.

In the physicochemical data, NMR represents nuclear magnetic resonance spectrum, wherein values are shown as δ (delta) values in ppm which are ordinarily used for indicating chemical shifts. TMS (tetramethylsilane) was used as an internal standard. Parenthesized numbers following δ values indicate the numbers of hydrogen atoms, and as to symbols after the parenthesized number, “s” represents singlet; “d” represents doublet; “t” represents triplet; “q” represents quartet; “m” represents multiplet, and “br” represents a broad absorption peak.

IR represents infrared absorption spectrum, and the spectrum was measured as a potassium bromide tablet unless otherwise specified. Numerical values are indicated as wave numbers in cm⁻¹. Only major absorption peaks are indicated. The symbol “mp” means melting point, and uncorrected values as 0° C. are indicated.

Example 1 Synthesis of trans-4-amino-[(S)-N-[(S)-2-propoxycarbonylamino-3-isopropylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 51 in Table 1) hydrochloride

a) Trans-4-t-butoxycarbonylamino-benzyloxycarbonylaminomethylcyclohexane

To a solution of trans-4-aminomethylcyclohexanecarboxylic acid (15.7 g, 100 mmol) and sodium hydroxide (4.0 g, 100 mmol) in water (30 ml), benzyloxycarbonyl chloride (15.6 ml, 110 mmol) and a solution of sodium hydroxide (4.4 g, 110 mmol) in water (30 ml) were simultaneously and slowly added dropwise at 0° C. After stirring was continued for four hours, the mixture was extracted once with ether, and 1N hydrochloric acid was added to the aqueous layer to adjust its pH to 2. The deposited white solid was collected by filtration and dried.

Triethylamine (8.3 ml, 60 mmol) and DPPA (13.7 g, 50 mmol) were added to a solution of the above-obtained compound (12.8 g, 50 mmol) in t-butanol (150 ml), and the mixture was heated under reflux for eight hours. After the solvent was evaporated, the residue was added with water, and then the mixture was extracted with chloroform. The organic layer was washed once with 5% aqueous sodium carbonate, once with 5% aqueous acid potassium sulfate, twice with water, and then once with saturated brine. After the layer was dried over sodium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound a) (8.6 g, yield; 47%).

NMR (CDCl₃): 0.85-1.37 (m, 14H), 1.60-1.85 (m, 4H), 2.84 (t, 1H), 3.12 (br, 1H), 5.00 (s, 2H), 6.62 (d, 1H), 7.23-7.39 (m, 6H).

b) Trans-4-t-butoxycarbonylamino-[(S)-N-benzyloxycarbonylprolyl]aminomethylcyclohexane

The compound obtained in a) (4.4 g, 12 mmol) was dissolved in methanol (200 ml), and the solution was subjected to catalytic reduction in the presence of palladium black (0.4 g) at ambient temperature under atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration, and the solvent was evaporated.

CDI (2.0 g, 12 mmol) was added to a solution of (S)-Z-proline (3.0 g, 12 mmol) in THF (30 ml) at 0° C. After stirring was continued for three hours, the mixture was added with a solution of the above-obtained compound in THF (150 ml) at 0° C. After stirring for six hours, the solvent was evaporated, and the residue was added with water (50 ml). The mixture was extracted with chloroform, and the organic layer was washed three times with water and once with saturated brine. After the layer was dried with sodium sulfate, the solvent was evaporated. The residue was purified by silica gel chromatography (chloroform/methanol) to obtain the title compound b) (4.2 g, yield; 77%).

NMR (CDCl₃): 0.85-1.06 (m, 4H), 1.44 (s, 9H), 1.60-2.35 (m, 9H), 2.94-3.20 (m, 2H), 3.20-3.55 (m, 3H), 4.31 (br, 1H), 4.47 (br, 1H), 5.14 (s, 2H), 6.90 (br, 1H), 7.15-7.40 (m, 5H)

c) Trans-4-t-butoxycarbonylamino-[(S)-N-[(S)-2-propoxycarbonylamino-3-isopropylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane

The compound obtained in b) (3.6 g 7.9 mmol) was dissolved in methanol (50 ml), and the solution was subjected to catalytic reduction in the presence of palladium black (0.3 g) at ambient temperature under atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration, and then the solvent was evaporated.

The oily product obtained above, (S)-2-propoxycarbonylamino-3-isopropylthio-3-methylbutanoic acid (2.4 g, 8.7 mmol), and triethylamine (1.58 g, 15.6 mmol) were dissolved in dichloromethane (55 ml), and the solution was added dropwise with a solution of diethyl phosphorocyanidate (DEPC, 1.4 g, 8.7 mmol) in dichloromethane (10 ml) at 0° C. After the temperature was raised up to room temperature, the mixture was stirred for an additional 24 hours and then added with water. The mixture was extracted twice with dichloromethane, and the organic layer was dried over sodium sulfate.

After the solvent was evaporated, the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound c) (3.9g, yield; 85%).

NMR (CDCl₃): 7.18 (t, 1H), 5.59 (d, 1H), 4.61 (d, 1H), 4.34 (d, 2H), 4.20-3.85 (m, 3H), 3.72 (m, 1H), 3.33 (m, 1H), 3.90-3.20 (m, 3H), 2.37 (m, 1H), 2.10-0.90 (m, 14H), 1.47 (s, 3H), 1.43 (s, 9H), 1.40 (s, 3H), 1.29 (dd, 6H), 0.94 (t, 3H).

d) Trans-4-amino-[(S)-N-[(S)-2-propoxycarbonylamino-3-isopropylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane hydrochloride

A solution of the compound obtained in c) (3.9 g, 6.7 mmol) in chloroform (5 ml) was added dropwise with a 4N solution of hydrochloric acid in ethyl acetate (37 ml) at 0° C. After the mixture was stirred for one hour, the solvent was evaporated. The resulting residue was suspended and washed in ether, and then collected by filtration to obtain the title compound d) (3.1 g, yield; 90%).

NMR (CDCl₃): 8.34 (br, 3H), 7.21 (t, 1H), 5.61 (d, 1H), 4.59 (d, 1H), 4.31 (d, 1H), 4.07-3.92 (m, 3H), 3.74 (m, 1H), 3.20-2.90 (m, 2H), 2.36 (m, 1H), 2.20-1.40 (m, 12H), 1.47 (s, 3H), 1.29 (dd, 6H), 0.95 (t, 3H), 1.10-0.90 (m, 2H); IR: 3344, 2974, 2876, 1689, 1637, 1527, 1448, 1313, 1240, 1060.

In similar manners to those described above, the compounds of Examples 2-39 set out below were obtained.

Example 2 Trans-4-amino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-isopropylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 50 in Table 1) hydrochloride

NMR (CDCl₃): 8.32 (br, 3H), 7.22 (t, 1H), 5.60 (d, 1H), 4.59 (m, 1H), 4.30 (d, 1H), 4.20-3.90 (m, 3H), 3.71 (m, 1H), 3.20-2.89 (m, 4H), 2.36 (m, 1H), 2.16 (m, 2H), 2.05 (m, 3H), 1.90-1.20 (m, 5H), 1.47 (s, 3H), 1.40 (s, 3H), 1.34-1.21 (m, 9H), 1.05-0.91 (m, 2H); IR: 3352, 2934, 2872, 1693, 1637, 1535, 1444, 1367, 1302, 1242.

Example 3 Trans-4-amino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-isobutylthio-3-methylbutanoyl]proly]aminomethylcyclohexane (Compound No. 97 in Table 1) hydrochloride

NMR (CDCl₃): 8.32 (br, 3H), 7.19 (t, 1H), 5.58 (d, 1H), 4.57 (d, 1H), 4.30 (d, 2H), 3.93 (m, 1H), 3.76 (m, 1H), 3.20-2.90 (m, 3H), 2.47-2.30 (m, 3H), 2.25-2.15 (m, 2H), 2.10-1.40 (m, 9H), 1.48 (s, 3H), 1.38 (s, 3H), 1.27 (t, 3H), 0.98 (dd, 6H), 1.05-0.90 (m, 2H); IR: 3354, 2957, 2868, 1691, 1639, 1535, 1444, 1386, 1242, 1055.

Example 4 Trans-4-amino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-isopropylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 52 in Table 1) hydrochloride

NMR (CDCl₃): 8.33 (br, 3H), 7.24 (t, 1H), 5.53 (d, 1H), 4.82 (m, 1H), 4.59 (m, 1H), 4.28 (d, 1H), 3.97 (m, 1H), 3.71 (m, 1H), 3.12-2.85 (m, 4H), 2.35 (m, 1H), 2.20 (m, 2H), 2.15-1.40 (m, 8H), 1.48 (s, 3H), 1.40 (s, 3H), 1.29 (dd, 6H), 1.26 (d, 6H), 1.10-0.90 (m, 2H); IR: 3344, 2935, 2866, 1685, 1637, 1523, 1446, 1242, 1111, 1043.

Example 5 Trans-4-amino-[(S)-N-[(S)-2-methoxycarbonylamino-3-ethylthio-3-methyl-butanoyl]prolyl]aminomethylcyclohexane (Compound No. 12 in Table 1) hydrochloride

NMR (CDCl₃): 8.31 (br, 3H), 7.19 (t, 1H), 5.68 (d, 1H), 4.57 (d, 1H), 4.35 (d, 1) 3.91 (m, 1H), 3.74 (m, 1H), 3.69 (s, 3H), 3.22-2.94 (m, 3H), 2.70 -2.45(m, 3H), 2.40-1.40 (m, 10H), 1.44 (s, 3H), 1.39 (s, 3H), 1.21 (t, 3H), 1.10 -0.90 (m, 2H); IR: 3383, 2935, 2872, 1701, 1637, 1541, 1448, 1298, 1244, 1057.

Example 6 Trans-4-amino-[(S)-N-[(S)-2-methoxycarbonylamino-3-isopropylthio-3-methylbutanoyl]proly]aminomethylcyclohexane (Compound No. 49 in Table 1) hydrochloride.

NMR (CDCl₃): 8.32 (br, 3H), 7.18 (t, 1H), 5.67 (d, 1H), 4.58 (d, 1H), 4.33 (d, 1H), 3.94 (m, 1H), 3.70 (m, 1H), 3.69 (s, 1H), 3.20-2.94 (m, 4H), 2.37 (m, 1H), 2.20-1.40 (m, 10H), 1.47 (s, 3H), 1.40 (s, 3H), 1.29 (dd, 6H), 1.10-0.90 (m, 2H); IR: 3356, 2934, 2868, 1701, 1643, 1535, 1446, 1300, 1242, 1053.

Example 7 Trans-4-amino-[(S)-N-[(S)-2-methoxycarbonylamino-3-cyclopentylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 163 in Table 1) hydrochloride

NMR (CDCl₃): 8.33 (br, 3H), 7.21 (t, 1H), 5.64 (d, 1H), 4.59 (d, 1H), 4.34 (d, 1H), 3.94 (m, 1H), 3.72 (m, 1H), 3.69 (s, 3H), 3.20-2.90 (m, 4H), 2.38 (m, 1H), 2.20-1.20 (m, 18H), 1.47 (s, 3H), 1.39 (s, 3H), 1.10-0.90 (m, 2H); IR: 3362, 2955, 2868, 1701, 1639, 1535, 1446, 1298, 1242, 1055.

Example 8 Trans-4-amino-[(S)-N-[(S)-2-methylsulfonylamino-3-ethylthio-3-methyl-butanoyl]prolyl]aminomethylcyclohexane (Compound No. 23 in Table 1) hydrochloride

NMR (CDCl₃): 8.13 (br, 3H), 6.99 (t, 1H), 5.97 (d, 1H), 4.52 (d, 1H), 4.25 (t, 1H), 4.15 (d, 1H), 4.03-3.81 (m, 2H), 3.20-2.90 (m, 3H), 3.08 (s, 3H), 2.70-2.50 (m, 2H), 2.50-1.40 (m, 10H), 1.42 (s, 3H), 1.39 (s, 3H), 1.29-1.16 (m, 3H), 1.10-0.90 (m, 2H); IR: 3383, 2934, 2866, 1637, 1543, 1450, 1317, 1151, 1035, 983.

Example 9 Trans-4-amino-[(S)-N-[(S)-2-amino-3-ethylthio-3-methylbutanoyl]prolyl]-aminomethylcyclohexane (Compound No. 8 in Table 1) dihydrochloride

NMR (CDCl₃): 8.72 (br, 3H), 8.31 (t, 1H), 8.18 (br, 3H), 4.44 (m, 1H), 4.27 (m, 1H), 4.06 (d, 1H), 3.83-3.60 (m, 4H), 3.13 (m, 1H), 3.04-2.87 (m, 2H), 2.61-2.52 (m, 2H), 2.24-1.40 (m, 8H), 1.47 (s, 3H), 1.42 (s, 3H), 1.29-1.22 (m, 3H), 1.10-0.90 (m, 2H); IR: 3476, 3285, 3084, 2941, 1647, 1493, 1446, 1346, 1116, 1049.

Example 10 Trans-4-amino-[(S)-N-[(S)-2-methoxycarbonylamino-3-propylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 30 in Table 1) hydrochloride

NMR (CDCl₃): 8.31 (br, 3H), 7.16 (t, 1H), 5.64 (d, 1H), 4.58 (d, 1H), 4.34 (d, 1H), 3.91 (m, 1H), 3.76 (m, 1H), 3.69 (s, 3H), 3.20-2.90 (m, 3H), 2.60-2.34 (m, 3H), 2.14 (m, 2H), 2.10-1.40 (m, 10H), 1.43 (s, 3H), 1.39 (s, 3H), 0.99 (t, 3H), 1.10-0.90 (m, 2H); IR: 3358, 2935, 2866, 1703, 1643, 1533, 1446, 1298, 1240, 1055.

Example 11 Trans-4-amino-[(S)-N-[(S)-2-methoxycarbonylamino-3-isobutylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 96 in Table 1) hydrochloride

NMR (CDCl₃): 8.33 (br, 3H), 7.16 (t, 1H), 5.64 (d, 1H), 4.57 (d, 1H), 4.33 (d, 1H), 3.91 (m, 1H), 3.75 (m, 1H), 3.69 (s, 3H), 3.20-2.90 (m, 3H), 2.50-2.30 (m, 3H), 2.15 (m, 2H), 2.10-1.40 (m, 9H), 1.42 (s, 3H), 1.38 (s, 3H), 0.98 (dd, 6H), 1.10-0.90 (m, 2H); IR: 3429, 2957, 2868, 1701, 1639, 1541, 1448, 1321, 1244, 1055.

Example 12 Trans-4-amino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-ethylthio-3-methyl-butanoyl]prolyl]aminomethylcyclohexane (Compound No. 13 in Table 1) hydrochloride

NMR (CDCl₃): 8.33 (br, 3H), 7.17 (t, 1H), 5.57 (d, 1H), 4.57 (d, 1H), 4.33 (d, 1H), 4.22-4.05 (m, 2H), 3.91 (m, 1H), 3.82 (m, 1H), 3.20-2.90 (m, 3H), 2.70-2.50 (m, 2H), 2.36 (m, 1H), 2.22-1.40 (m, 10H), 1.44 (s, 3H), 1.39 (s, 3H), 1.27 (t, 3H), 1.22 (t, 3H), 1.20-0.90 (m, 2H); IR: 3354, 2934, 2872, 1701, 1637, 1523, 1444, 1298, 1242, 1057.

Example 13 Trans-4-amino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-propylthio-3-methyl-butanoyl]prolyl]aminomethylcyclohexane (Compound No. 31 in Table 1) hydrochloride

NMR (CDCl₃): 8.33 (br, 3H), 7.18 (t, 1H), 5.57 (d, 1H), 4.58 (d, 1H), 4.32 (d, 1H), 4.22-4.05 (m, 2H), 3.96 (m, 1H), 3.76 (m, 1H), 3.20-2.90 (m, 3H), 2.60-2.47 (m, 2H), 2.36 (m, 1H), 2.25-1.40 (m, 12H), 1.49 (s, 3H), 1.43 (s, 3H), 1.30 (t, 3H), 1.00 (t, 3H), 1.16-0.91 (m, 2H); IR: 3441, 2939, 1641, 1533, 1442, 1300, 1242, 1192, 1170, 1055.

Example 14 Trans-4-amino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-cyclopentylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 164 in Table 1) hydrochloride

NMR (CDCl₃): 8.32 (br, 3H), 7.23 (t, 1H), 5.60 (d, 1H), 4.59 (d, 1H), 4.31 (d, 1H), 4.17-4.02 (m, 2H), 3.95 (m, 1H), 3.71 (m, 1H), 3.22-2.94 (m, 4H), 2.36 (m, 1H), 2.36 (m, 1H), 2.26-1.40 (m, 18H), 1.47 (s, 3H), 1.39 (s, 3H), 1.27 (t, 3H), 1.10-0.90 (m, 2H); IR: 3346, 2939, 2868, 1695, 1641, 1533, 1444, 1300, 1240, 1055.

Example 15 Trans-4-amino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-phenylmethylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 214 in Table 1) hydrochloride

NMR (CDCl₃): 8.32 (br, 3H), 7.35-7.24 (m, 5H), 7.16 (t, 1H), 5.57 (d, 1H), 4.56 (d, 1H), 4.22 (d, 1H), 4.20-4.05 (m, 2H), 3.85 (m, 1H), 3.78 (d, 2H), 3.85 (m, 1H), 3.62 (m, 1H), 3.20-2.90 (m, 3H), 2.32 (m, 1H), 2.25-1.40 (m, 10H), 1.46 (s, 3H), 1.40 (s, 3H), 1.30 (t, 3H), 1.20-0.90 (m, 2H) IR: 3348, 2935, 2874, 1697, 1637, 1541, 1448, 1298, 1242, 1055.

Example 16 Trans-4-amino-[(S)-N-[(S)-2-propoxycarbonylamino-3-propylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 32 in Table 1) hydrochloride

NMR (CDCl₃): 8.33 (br, 3H), 7.19 (t, 1H), 5.57 (d, 1H), 4.57 (d, 1H), 4.31 (d, 1H), 4.11-3.87 (m, 3H), 3.74 (m, 1H), 3.20-2.90 (m, 3H), 2.60-2.40 (m, 2H), 2.34 (m, 1H), 2.15 (m, 2H), 2.10-1.40 (m, 12H), 1.43 (s, 3H), 1.39 (s, 3H), 0.99 (t, 3H), 0.95 (t, 3H), 1.10-0.90 (m, 2H); IR: 3344, 2964, 2878, 1695, 1639, 1529, 1442, 1296, 1240, 1060.

Example 17 Trans-4-amino-[(S)-N-[(S)-2-propoxycarbonylamino-3-cyclopentylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 165 in Table 1) hydrochloride

NMR (CDCl₃): 8.32 (br, 3H), 7.21 (t, 1H), 5.59 (d, 1H), 4.58 (d, 1H), 4.32 (d, 1H), 4.13-3.93 (m, 3H), 3.74(m, 1H), 3.21-2.90(m, 4H), 2.34(m, 1H), 2.25-1.40 (m, 20H), 1.47 (s, 3H), 1.39 (s, 3H), 0.95 (t, 3H), 1.10-0.90 (m, 2H); IR: 3348, 2959, 2870, 1693, 1641, 1529, 1446, 1294, 1240, 1060.

Example 18 Trans-4-amino-[(S)-N-[(S)-2-propoxycarbonylamino-3-isobutylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 98 in Table 1) hydrochloride

NMR (CDCl₃): 8.30 (br, 3H), 7.25 (t, 1H), 5.61 (d, 1H), 4.57 (d, 1H), 4.29 (d, 1H), 3.90 (m, 3H), 3.74 (m, 1H), 3.20-2.90 (m, 1H), 2.40 (m, 2H), 2.30 (m, 1H), 2.16 (m, 2H), 2.10-1.40 (m, 11H), 1.42 (s, 3H), 1.39 (s, 3H), 0.98 (d, 6H), 0.94 (t, 3H), 1.10-0.90 (m, 2H); IR: 3356, 2934, 2883, 1693, 1637, 1527, 1448, 1298, 1240, 1060.

Example 19 Trans-4-amino-[(S)-N-[(S)-2-propoxycarbonylamino-3-butylthio-3-methyl-butanoyl]prolyl]aminomethylcyclohexane (Compound No. 79 in Table 1) hydrochloride

NMR (CDCl₃): 8.32 (br, 3H), 7.19 (t, 1H), 5.58 (d, 1H), 4.56 (d, 1H), 4.32 (d, 1H), 3.90 (m, 3H), 3.74 (m, 1H), 3.20-2.90 (m, 3H), 2.65-2.46 (m, 2H), 2.34(m, 1H), 2.16 (m, 2H), 2.10-1.40 (m, 14H), 1.43 (s, 3H), 1.39 (s, 3H), 0.95 (t, 3H), 0.92 (t, 3H), 1.10-0.90 (m, 2H); IR: 3344, 2934, 2874, 1695, 1641, 1529, 1439, 1296, 1240, 1060.

Example 20 Trans-4-amino-[(S)-N-[(S)-2-propoxycarbonylamino-3-cyclohexylmethyl-thio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 241 in Table 1) hydrochloride

NMR (CDCl₃): 8.31 (br, 3H), 7.20 (t, 1H), 5.59 (d, 1H), 4.58 (d, 1H), 4.30 (d, 1H), 4.15-3.90 (m, 3H), 3.77 (m, 1H), 3.20-2.90 (m, 3H), 2.47-2.30 (m, 3H), (m, 3H), 2.18 (m, 2H), 2.10-1.20 (m, 19H), 1.42 (s, 3H), 1.38 (s, 3H), 0.95 (t, 3H), 1.10-0.90 (m, 2H); IR: 3350, 2926, 2852, 1697, 1639, 1533, 1448, 1302, 1240, 1060.

Example 21 Trans-4-amino-[(S)-N-[(S)-2-propoxycarbonylamino-3-cyclobutylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 126 in Table 1) hydrochloride

NMR (CDCl₃): 8.30 (br, 3H), 7.19 (t, 1H), 5.58 (d, 1H), 4.57 (d, 1H), 4.29 (d, 1H), 4.14-3.90 (m, 3H), 3.75(m, 1H), 3.22-2.92 (m, 3H), 2.51-2.32 (m, 3H), 2.25-1.20 (m, 17H), 1.42 (s, 3H), 1.38 (s, 3H), 0.95 (t, 3H), 1.10-0.90 (m, 2H); IR: 3358, 2972, 2874, 1697, 1639, 1535, 1440, 1294, 1240, 1060.

Example 22 Trans-4-amino-[(S)-N-[(S)-2-propoxycarbonylamino-3-(1-ethylpropyl)-thio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 182 in Table 1) hydrochloride

NMR (CDCl₃): 8.31 (br, 3H), 7.27 (t, 1H), 5.65 (d, 1H), 4.60 (d, 1H), 4.24(d, 1H), 4.16-3.88 (m, 3H), 3.67 (m, 1H), 3.22-3.00 (m, 2H), 2.95 (m, 1H), 2.54 (m, 1H), 2.35 (m, 1H), 2.17 (m, 2H), 2.10-1.40 (m, 17H), 1.44 (s, 3H), 1.41 (s, 3H), 0.98 (t, 3H), 1.10-0.90 (m, 2H); IR: 3425, 2966, 2878, 1701, 1641, 1537, 1446, 1292, 1240, 1060.

Example 23 Trans-4-amino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-phenylmethyl-thio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 216 in Table 1) hydrochloride

NMR (CDCl₃): 8.33 (br, 3H), 7.32 (m, 5H), 7.21 (br, 1H), 5.52 (br, 1H), 4.80 (m, 1H), 4.58 (d, 1H), 4.21 (d, 1H), 3.80 (m, 3H), 3.61 (m, 1H), 3.22-2.90 (m, 3H), 2.40-2.18 (m, 3H), 2.10-1.76 (m, 4H), 1.47 (s, 3H), 1.41 (s, 3H), 1.62-1.39 (m, 4H), 1.26 (m, 6H), 0.99 (m, 2H); IR: 3349, 2978, 2935, 1692, 1644, 1497, 1453, 1242, 1111.

Example 24 Trans-4-amino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-propylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 33 in Table 1) hydrochloride

NMR (CDCl₃): 8.32 (br, 3H), 7.20 (br, 1H), 5.50 (d, 1H), 4.83 (m, 1H), 4.57 (d, 1H), 4.32 (d, 1H), 3.92 (m, 1H), 3.77 (m, 1H), 3.11 (m, 2H), 2.98 (m, 1H), (m, 1H), 2.50 (m, 2H), 2.37 (m, 1H), 2.20 (m, 2H), 2.07-1.78 (m, 5H), 1.56 (m, 5H), 1.43 (s, 3H), 1.39 (s, 3H), 1.26 (d, 3H), 1.24 (d, 3H), 0.99 (t, 3H), 0.98 (m, 2H); IR: 3345, 2936, 1688, 1640, 1534, 1447, 1242, 1111.

Example 25 Trans-4-amino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-butylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 80 in Table 1) hydrochloride

NMR (CDCl₃): 8.31 (br, 3H), 7.21 (br, 1H), 5.51 (d, 1H), 4.83 (m, 1H), 4.57 (d, 1H), 4.32 (d, 1H), 3.93 (m, 1H), 3.77 (m, 1H), 3.20-2.90 (m, 3H), 2.53 (m, 2H), 2.38 (m, 1H), 2.17 (m, 2H), 1.99 (m, 5H), 1.83 (m, 2H), 1.51 (m, 5H), 1.43 (s, 3H), 1.38 (s, 3H), 1.26 (d, 3H), 1.24 (d, 3H), 1.04-0.90 (m, 2H), 0.92 (t, 3H); IR: 3346, 2934, 2872, 1686, 1638, 1541, 1439, 1242, 1111.

Example 26 Trans-4-amino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-isobutylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 99 in Table 1) hydrochloride

NMR (CDCl₃): 8.32 (br, 3H), 7.23 (br, 1H), 5.51 (d, 1H), 4.82 (m, 1H), 4.58 (d, 1H), 4.29 (d, 1H), 3.95 (m, 1H), 3.75 (m, 1H), 3.12 (m, 1H), 2.96 (m, 1H), 2.42 (m, 1H), 2.35 (m, 2H), 2.18 (m, 2H), 1.99 (m, 2H), 1.81 (m, 5H), 1.51 (m, 2H), 1.42 (s, 3H), 1.38 (s, 3H), 1.26 (d, 3H), 1.24 (d, 3H), 1.00 (d, 3H), 0.98 (d, 3H), 0.98 (m, 2H); IR: 3345, 2957, 1688, 1640, 1626, 1449, 1242, 1111.

Example 27 Trans-4-amino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-cyclopentylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 172 in Table 1) hydrochloride

NMR (CDCl₃): 8.31 (br, 3H), 7.23 (br, 1H), 5.53 (d, 1H), 4.83 (m, 1H), 4.59 (d, 1H), 4.32 (d, 1H), 3.94 (m, 1H), 3.74 (m, 1H), 3.09 (m, 3H), 2.94 (m, 1H), 2.39 (m, 1H), 2.19 (m, 2H), 1.99 (m, 5H), 1.83 (m, 2H), 1.71 (m, 2H), 1.54 (m, 7H), 1.46 (s, 3H), 1.46 (s, 3H), 1.39 (s, 3H), 1.26 (d, 3H), 1.24 (d, 3H), 1.00 (m, 2H); IR: 3349, 2942, 2868, 1692, 1640, 1530, 1447, 1240, 1111.

Example 28 Trans-4-amino-[(S)-N-[(S)-2-isobutyloxycarbonylamino-3-cyclopentylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 167 in Table 1) hydrochloride

NMR (CDCl₃): 8.31 (br, 3H), 7.21 (t, 1H), 5.62 (d, 1H), 4.57 (d, 1H), 4.33 (d, 1H), 4.00-3.85 (m, 2H), 3.85-3.70 (m, 2H), 3.20-2.85 (m, 4H), 2.40-1.40 (m, 20H), 1.47 (s, 3H), 1.43 (s, 3H), 1.10-0.90 (m, 2H), 0.94 (d, 6H); IR: 3356, 2966, 2874, 1701, 1637, 1541, 1458, 1296, 1240, 1059.

Example 29 Trans-4-amino-[(S)-N-[(S)-2-isobutyloxycarbonylamino-3-isopropylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 54 in Table 1) hydrochloride

NMR (CDCl₃): 8.31 (br, 3H), 7.21 (t, 1H), 5.63 (d, 1H), 4.58 (d, 1H), 4.31(d, 1H), 4.05-3.85 (m, 2H), 3.80-3.70 (m, 2H), 3.20-2.90 (m, 4H), 2.34 (m, 1H), 2.20-1.40 (m, 11H), 1.47 (s, 3H), 1.40 (s, 3H), 1.30 (dd, 6H), 0.93 (d, 6H), 1.10-0.90 (m, 2H) IR: 3346, 2935, 2876, 1699, 1637, 1527, 1448, 1292, 1240, 1053.

Example 30 Trans-4-amino-[(S)-N-[(S)-2-propoxycarbonylamino-3-(3′-methylbutyl-thio)-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 255 in Table 1) hydrochloride

NMR (CDCl₃): 8.32 (br, 3H), 7.19 (t, 1H), 5.59 (d, 1H), 4.58 (d, 1H), 4.32 (d, 1H), 4.15-3.90 (m, 3H), 3.80 (m, 1H), 3.20-2.90 (m, 3H), 2.65-2.45 (m, 2H), 2.35 (m, 1H), 2.30-1.40 (m, 15H), 1.43 (s, 3H), 1.38 (s, 3H), 0.95 (t, 3H), 0.90 (d, 6H), 1.10-0.90 (m, 2H); IR: 3354, 2934, 2874, 1701, 1637, 1541, 1439, 1298, 1240, 1060.

Example 31 Trans-4-amino-[(S)-N-[(S)-2-isobutyloxycarbonylamino-3-propylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 35 in Table 1) hydrochloride

NMR (CDCl₃): 8.32 (br, 3H), 7.19 (t, 1H), 5.60 (d, 1H), 4.57 (d, 1H), 4.33 (d, 1H), 3.89 (dd, 2H), 3.77 (m, 2H), 3.20-2.90 (m, 3H), 2.62-2.45 (m, 2H), 2.34 (m, 1H), 2.18 (m, 2H), 2.10-1.40 (m, 11H), 1.43 (s, 3H), 1.39 (s, 3H), 0.99 (t, 3H), 0.93 (d, 6H), 1.10-0.90 (m, 2H); IR: 3346, 2962, 2878, 1693, 1637, 1527, 1448, 1294, 1240, 1053.

Example 32 Trans-4-amino-[(S)-N-[(S)-2-isobutyloxycarbonylamino-3-isobutylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 101 in Table 1) hydrochloride

NMR (CDCl₃): 8.31 (br, 3H), 7.19 (t, 1H), 5.60 (d, 1H), 4.58 (d, 1H), 4.31 (d, 1H), 4.00-3.85 (m, 2H), 3.75 (m, 2H), 3.20-2.90 (m, 3H), 2.18 (m, 2H), 2.10-1.40 (m, 10H), 1.42 (s, 3H), 1.39 (s, 3H), 0.98 (dd, 6H), 0.94(d, 6H), 1.10-0.90 (m, 2H); IR: 3346, 2959, 2870, 1701, 1637, 1533, 1448, 1294, 1242, 1053.

Example 33 Trans-4-amino-[(S)-N-[(S)-2-isobutyloxycarbonylamino-3-ethylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 17 in Table 1) hydrochloride

NMR (CDCl₃): 8.31 (br, 3H), 7.18 (t, 1H), 5.62 (d, 1H), 4.58 (d, 1H), 4.34 (d, 1H), 4.00-3.85 (m, 2H), 3.85-3.70 (m, 2H), 3.20-2.90 (m, 3H), 2.70-2.50 (m, 2H), 2.35 (m, 1H), 2.20-1.40 (m, 11H), 1.43 (s, 3H), 1.39 (s, 3H), 1.22 (t, 3H), 0.94 (d, 6H), 1.10-0.90 (m, 2H); IR: 3346, 2962, 2874, 1697, 1643, 1529, 1446, 1294, 1240, 1055.

Example 34 Trans-4-amino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-ethylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 15 in Table 1) hydrochloride

NMR (CDCl₃): 8.32 (br, 3H), 7.26 (t, 1H), 5.69 (d, 1H), 4.82 (m, 1H), 4.55 (d, 1H), 3.94 (m, 1H), 3.77 (m, 1H), 3.18-2.85 (m, 3H), 2.65-2.45 (m, 2H), 2.31 (m, 1H), 2.20-1.40 (m, 10H), 1.44 (s, 3H), 1.39 (s, 3H), 1.28-1.17 (m, 9H), 1.10-0.90 (m, 2H); IR: 3406, 2978, 2874, 1687, 1637, 1541, 1448, 1255, 1111, 1039.

Example 35 Trans-4-amino-[(S)-N-[(S)-2-butoxycarbonylamino-3-propylthio-3-methyl-butanoyl]prolyl]aminomethylcyclohexane (Compound No. 34 in Table 1) hydrochloride

NMR (CDCl₃): 8.32 (br, 3H), 7.18 (br, 1H), 5.58 (d, 1H), 4.57 (d, 1H), 4.34 (d, 1H), 4.11 (m, 1H), 3.98 (m, 2H), 3.78 (m, 1H), 3.16-2.94 (m, 3H), 2.50 (m, 2H), 2.36 (m, 1H), 2.18 (m, 2H), 2.00 (m, 4H), 1.84 (m, 2H), 1.58 (m, 7H), 1.48-1.30 (m, 2H), 1.43 (s, 3H), 1.39 (s,3H), 1.10-0.90 (m, 2H), 0.99 (t, 3H), 0.94 (t, 3H); IR: 3428, 3349, 2961, 2936, 1690, 1640, 1535, 1449, 1242, 1065.

Example 36 Trans-4-amino-[(S)-N-[(S)-2-butoxycarbonylamino-3-isopropylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 53 in Table 1) hydrochloride

NMR (CDCl₃): 8.32 (br, 3H), 7.18 (br, 1H), 5.58 (d, 1H), 4.58 (d, 1H), 4.32 (d, 1H), 4.11 (m,1H), 3.97 (m, 2H), 3.75 (m, 1H), 3.10-3.00 (m, 2H), 3.00 (m, 2H), 2.38 (m, 1H), 2.16 (m, 2H), 2.08 (m, 4H), 1.84 (m, 4H), 1.61 (m, 2H), 1.56-1.40 (m, 2H), 1.42 (s, 3H), 1.37 (s, 3H), 1.32 (d, 3H), 1.26 (d, 3H), 1.04-0.90 (m, 2H), 0.94 (t, 3H); IR: 3349, 3341, 2959, 2934, 1690, 1638, 1524, 1449, 1242, 1065.

Example 37 Trans-4-amino-[(S)-N-[(S)-2-butoxycarbonylamino-3-butylthio-3-methyl-butanoyl]prolyl]aminomethylcyclohexane (Compound No. 81 in Table 1) hydrochloride

NMR (CDCl₃): 8.30 (br, 3H), 7.18 (br, 1H), 5.58 (d, 1H), 4.55 (d, 1H), 4.33 (d, 1H), 4.08 (m, 1H), 4.04-3.86 (m, 2H), 3.70 (m, 1H), 3.12-2.90 (m, 3H), 2.52 (m, 2H), 2.36 (m, 1H), 2.16 (m, 2H), 1.98 (m, 3H), 1.80 (m, 2H), 1.64-1.30 (m, 9H), 1.43 (s, 3H), 1.38 (s, 3H), 1.04-0.90 (m, 2H), 0.94 (t, 3H), 0.91 (t, 3H); IR: 3345, 2959, 2872, 1692, 1640, 1535, 1449, 1242, 1065.

Example 38 Trans-4-amino-[(S)-N-[(S)-2-butoxycarbonylamino-3-isobutylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 100 in Table 1) hydrochloride

NMR (CDCl3): 8.31 (br, 3H), 7.19 (br, 1H), 5.58 (d, 1H), 4.57 (d, 1H), 4.32 (d, 1H), 4.10 (m, 1H), 3.96 (m, 2H), 3.78 (m, 1H), 3.09 (m, 2H), 2.99 (m, 1H), 2.41 (m, 1H), 2.35 (m, 2H), 2.20 (m, 2H), 1.99 (m, 3H), 1.89-1.75 (m, 3H), 1.62 (m, 3H), 1.58-1.36 (m, 4H), 1.42 (s, 3H), 1.38 (s, 3H), 1.00-0.90 (m, 2H), 0.99 (d, 6H), 0.94 (t, 3H); IR: 3445, 2959, 1686, 1638, 1541, 1449, 1242, 1065.

Example 39 Trans-4-amino-[(S)-N-[(S)-2-pentyloxycarbonylamino-3-isopropylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 56 in Table 1) hydrochloride

NMR (CDCl₃): 8.34 (br, 3H), 7.20 (br, 1H), 5.60 (d, 1H), 4.60 (d, 1H), 4.31 (d, 1H), 4.03 (m, 2H), 4.03 (m, 1H), 3.80 (m, 1H), 3.28-3.06 (m, 4H), 2.46 (m, 1H), 2.28 (m, 2H), 2.06 (m, 4H), 1.92 (m, 4H), 1.70 (m, 4H), 1.62-1.46 (m, 2H), 1.48 (s, 3H), 1.41 (s, 3H), 1.32 (d, 3H), 1.26 (d, 3H), 1.10-1.00 (m, 2H), 0.92 (t, 3H); IR: 3428, 3347, 2957, 2934, 1690, 1640, 1524, 1449, 1240, 1055.

Example 40 Trans-4-amidino-[(S)-N-[(S)-2-propoxycarbonylamino-3-isopropylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 410 in Table 1) hydrochloride

a) Trans-4-N-benzyloxycarbonylaminomethyl-cyclohexylnitrile

To a solution of trans-4-aminomethylcyclohexanecarboxylic acid (25 g, 159 mmol) and sodium carbonate (20 g, 191 mmol) in water (300 ml), benzyloxycarbonyl chloride (27 ml, 190 mmol) was added at 0° C. After stirring was continued for six hours, the mixture was added with 1N hydrochloric acid to adjust its pH to 2, and the deposited white solid was collected by filtration and washed with water, and then dried. The resulting white solid was dissolved in THF (300 ml), and the solution was added with CDI (21 g, 130 mmol) at 0° C. After stirring was continued for three hours, the reaction mixture was added dropwise to a mixture of concentrated aqueous ammonia (50 ml) and THF (150 ml) at 0° C. After stirring for five hours, the solvent was evaporated, and water (500 ml) was added to the residue. The deposited white solid was collected by filtration and washed with water, and then dried.

To a solution of the above-obtained compound in 1,2-dichloroethane (500 ml), thionyl chloride (19 ml, 260 mmol) was added, and then the mixture was heated at an internal temperature of 70° C. After stirring was continued for five hours, the reaction mixture was poured into iced water, and the mixture was neutralized with 1N aqueous sodium hydroxide. The mixture was extracted with chloroform, and the organic layer was washed twice with water and once with saturated brine, and then dried over sodium sulfate. After the solvent was evaporated, the resulting crude product was recrystallized (hexane/ethyl acetate) to obtain the title compound a) (22.8 g, 53%). mp 90-92° C.

b) Trans-4-(S)-prolylaminomethyl-cyclohexylnitrile

The compound obtained in the above a) was dissolved in ethanol (250 ml), and the solution was subjected to catalytic reduction in the presence of palladium black (1g) at ambient temperature under atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration, and then the solvent was evaporated.

To a solution of (S)-N-benzyloxycarbonylproline (20.7 g, 83 mmol) in THF (150 ml), CDI (13.5 g, 83 mmol) was added at 0° C. After stirring was continued for three hours, the mixture was added with a solution of the compound obtained by the above-described reduction in THF (200 ml) at 0° C. After the mixture was stirred for 12 hours, the solvent was evaporated, and chloroform (400 ml) was added to the resulting residue. The organic layer was washed three times with water and once with saturated brine, and then dried over sodium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol).

The resulting compound was dissolved in ethanol (250 ml), and the solution was subjected to catalytic reduction in the presence of palladium black (1 g) at ambient temperature under atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration, and the solvent was evaporated to obtain the title compound b) (18.8 g, yield; 95%).

NMR (DMSO-d₆): 0.88-1.06 (m, 2H), 1.38-1.52 (m, 3H), 1.68-2.03 (m, 7H), 2.20-2.40 (m, 1H), 2.52-2.67 (m, 1H), 2.80-3.20 (m, 4H), 4.03-4.10 (m, 1H), 7.53 (br, 1H), 8.65-8.70 (m, 1H);

c) Trans-4-[(S)-N-[(S)-2-propoxycarbonylamino-3-isopropylthio-3-methylbutanoyl]-prolyl]aminomethylcyclohexylnitrile

To a solution of the compound obtained in the above b) (1.04 g, 4.4 mmol), (S)-2-propoxycarbonylamino-3-isopropylthio-3-methylbutanoic acid (1.20 g, 4.3 mmol) and triethylamine (1.5 g, 14.8 mmol) in dichloromethane (35 ml), a solution of diethyl phosphorocyanidate (DEPC, 0.85 g, 5.3 mmol) in dichloromethane (5 ml) was added dropwise at 0° C. The temperature of the mixture was raised up to room temperature, and stirring was further continued for 24 hours. The reaction mixture was added with water, and the mixture was extracted twice with dichloromethane, and then the organic layer was dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound c) (1.77 g, yield; 83%).

NMR (CDCl₃): 7.18 (t, 1H), 5.58 (d, 1H), 4.61 (d, 1H), 4.33 (d, 1H), 4.20-3.85 (m, 3H), 3.73 (m, 1H), 3.20-2.90 (m, 3H), 2.45-2.30 (m, 2H), 2.15-1.20 (m, 12H), 1.47 (s, 3H), 1.41 (s, 3H), 1.29 (dd, 6H), 0.95 (t, 3H), 1.10-0.90 (m, 2H).

d) Trans-4-amidino-[(S)-N-[(S)-2-propoxycarbonylamino-3-isopropylthio-3-methyl-butanoyl]prolyl]aminomethylcyclohexane hydrochloride

To a solution of the compound obtained in the above c) (0.70 g, 1.42 mmol) in chloroform (2 ml), a saturated solution of hydrogen chloride in ethanol (10 ml) was added at 0° C., and then the mixture was left to stand at 0° C. for 48 hours. The solvent of the reaction mixture was evaporated, and the resulting residue was dissolved in methanol (15 ml), and then the solution was added with ammonium carbonate (1.0 g, 10.4 mmol) at 0° C. The temperature of the mixture was raised up to room temperature, and stirring was continued for six hours, and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound d) (0.71 g, yield; 92%).

NMR (CDCl₃): 8.87 (br, 2H), 8.57 (br, 2H), 7.48(t, 1H), 6.00(d, 1H), 4.59(d, 1H), 4.13 (m, 1H), 4.10-3.90 (m, 2H), 3.85-3.65 (m, 2H), 3.15 (m, 1H), 3.05-2.85 (m, 2H), 2.60 (m, 1H), 2.21 (m, 1H), 2.10-1.40 (m, 11H), 1.48 (s, 3H), 1.38 (s, 3H), 1.28 (dd, 6H), 0.93 (t, 3H), 1.10-0.90 (m, 2H); IR: 3325, 3084, 2930, 2874, 1693, 1637, 1521, 1446, 1240, 1062.

In similar manners to those described above, the compounds of Examples 40-76 set out below were obtained.

Example 41 Trans-4-amidino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-(1′-ethylpropylthio)-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 514 in Table 1) hydrochloride

NMR (CDCl₃): 8.83 (br, 2H), 8.72 (br, 2H), 7.52 (t, 1H), 5.98 (d, 1H), 4.61 (d, 1H), 4.30-4.15 (m, 3H), 4.00 (m, 1H), 3.71 (m, 1H), 3.18 (m, 1H), 2.89 (m, 1H), 2.70-2.50 (m, 2H), 2.24 (m, 1H), 2.10-1.40 (m, 17H), 1.45 (s, 3H), 1.37 (s, 3H), 1.28 (t, 3H), 1.10-0.90 (m, 2H), 0.96 (dt, 6H); IR: 3298, 3063, 2964, 2868, 1685, 1647, 1521, 1444, 1240, 1055.

Example 42 Trans-4-amidino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-propylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 393 in Table 1) hydrochloride

NMR (CDCl₃): 8.76 (br, 2H), 8.69 (br, 2H), 7.52 (t, 1H), 6.06 (d, 1H), 4.58 (d, 1H), 4.38 (d, 1H), 4.50-4.05 (m, 2H), 3.94 (m, 1H), 3.81 (m, 1H), 3.13 (m, 1H), 2.94 (m, 1H), 2.65 (m, 1H), 2.65-2.40 (m, 2H), 2.19 (m, 1H), 2.15-1.40 (m, 12H), 1.43 (s, 3H), 1.37 (s, 3H), 1.27 (t, 3H), 0.99 (t, 3H), 1.10-0.90 (m, 2H) IR: 3296, 3074, 2932, 2872, 1693, 1639, 1523, 1444, 1242, 1055.

Example 43 Trans-4-amidino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-isobutylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 452 in Table 1) hydrochloride

NMR (CDCl₃): 8.76 (br, 2H), 8.72 (br, 2H), 7.55 (t, 1H), 6.04 (d, 1H), 4.59(d, 1H), 4.36 (d, 1H), 4.30-4.05 (m, 2H), 3.96 (m, 1H), 3.77 (m, 1H), 3.06 (m, 1H), 2.96 (m, 1H), 2.62 (m, 1H), 2.50-2.30 (m, 2H), 2.20-1.40 (m, 12H), 1.42 (s, 3H), 1.36 (s, 3H), 1.27 (t, 3H) 0.98 (d, 6H), 1.10-0.90 (m, 2H) IR: 3296, 3086, 2959, 2930, 2870, 1687, 1639, 1527, 1444, 1242, 1055.

Example 44 Trans-4-amidino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-ethylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 378 in Table 1) hydrochloride

NMR (CDCl₃): 8.78 (br, 2H), 8.61 (br, 2H), 7.59 (t, 1H), 5.83 (d, 1H), 4.82 (m, 1H), 4.57 (d, 1H), 4.39 (d, 1H), 3.93 (m, 1H), 3.90-3.65 (m, 2H), 3.15-2.90 (m, 2H), 2.70-2.45 (m, 4H), 2.30-1.40 (m, 9H), 1.42 (s, 3H), 1.37 (s, 3H), 1.25 (d, 6H), 1.21 (t, 3H), 1.10-0.90 (m, 2H); IR: 3323, 3067, 2930, 2866, 1685, 1639, 1516, 1446, 1242, 1111.

Example 45 Trans-4-amidino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-isopropylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane hydrochloride

NMR (CDCl3): 8.74 (br, 2H), 8.68 (br, 2H), 7.62 (t, 1H), 5.84 (d, 1H), 4.83 (m, 1H), 4.57 (d, 1H), 4.36 (d, 1H), 3.98 (m, 1H), 3.71 (m, 1H), 3.10-2.90 (m, 3H), 2.62 (m, 1H), 2.50-1.40 (m, 11H), 1.46 (s, 3H), 1.37 (s, 3H), 1.28 (dd, 6H), 1.26 (d, 6H), 1.10-0.90 (m, 2H); IR: 3292, 3092, 2932, 2872, 1685, 1637, 1516, 1446, 1253, 1047.

Example 46 Trans-4-amidino-[(S)-N-[(S)-2-propoxycarbonylamino-3-ethylthio-3-methylbutanoyl]prolyl]aminocyclohexane (Compound No. 377 in Table 1) hydrochloride

NMR (CDCl₃): 8.78 (br, 2H), 8.65 (br, 2H), 7.54 (t, 1H), 6.06 (d, 1H), 4.60 (d, 1H), 3.98 (d, 1H), 4.20-3.65 (m, 4H), 3.12 (m, 1H), 2.96 (m, 1H), 2.70-2.50 (m, 4H), 2.30-1.40 (m, 12H), 1.43 (s, 3H), 1.37 (s, 3H), 1.21 (t, 3H), 0.94 (t, 3H), 1.10-0.90 (m, 2H); IR: 3288, 3061, 2924, 2876, 1685, 1641, 1520, 1444, 1240, 1062.

Example 47 Trans-4-amidino-[(S)-N-[(S)-2-methoxycarbonylamino-3-ethylthio-3-methylbutanoyl]proly]aminomethylcyclohexane (Compound No. 375 in Table 1) hydrochloride

NMR (CDCl₃): 8.77 (br, 4H), 7.53 (t, 1H), 6.25 (d, 1H), 4.61 (d, 1H), 4.35 (d, 1H), 3.94 (m, 1H), 3.81 (m, 1H), 3.74 (s, 3H), 3.22 (m, 1H), 2.87 (m, 1H), 2.70-2.40 (m, 3H), 2.20 (m, 1H), 2.10-1.40 (m, 11H), 1.45 (s, 3H), 1.37 (s, 3H), 1.21 (t, 3H), 1.10-0.90 (m, 2H); IR: 3279, 3072, 2932, 2864, 1689, 1639, 1527, 1446, 1242, 1059.

Example 48 Trans-4-amidino-[(S)-N-[(S)-2-methoxycarbonylamino-3-isopropylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 419 in Table 1) hydrochloride

NMR (CDCl₃): 8.84 (br, 2H), 8.77 (br, 2H), 7.49 (t, 1H), 6.17 (d, 1H), 4.62 (d, 1H), 4.35 (d, 1H), 3.99 (m, 1H), 3.75 (s, 3H), 3.70 (m, 1H), 3.24 (m, 1H), 2.96 (m, 1H), 2.87 (m, 1H), 2.53 (m, 1H), 2.23 (m, 1H), 2.10-1.40 (m, 10H), 1.49 (s, 3H), 1.37 (s, 3H), 1.26 (dd, 6H), 1.10-0.90 (m, 2H); IR: 3296, 3072, 2930, 2876, 1689, 1639, 1523, 1446, 1242, 1053.

Example 49 Trans-4-amidino-[(S)-N-[(S)-2-methoxycarbonylamino-3-propylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 392 in Table 1) hydrochloride

NMR (CDCl₃): 8.79 (br, 4H), 7.26 (t, 1H), 6.25 (d, 1H), 4.61 (d, 1H), 4.36 (d, 1H), 4.02 (m, 1H), 3.78 (m, 1H), 3.74 (s, 3H), 3.24 (m, 1H), 2.95 (m, 1H), 2.60 (m, 1H), 2.48 (q, 2H), 2.21 (m, 1H), 2.10-1.40 (m, 12H), 1.44 (s, 3H), 1.37 (s, 3H), 0.99 (t, 3H), 1.10-0.90 (m, 2H); IR: 3314, 3082, 2932, 2872, 1685, 1637, 1524, 1448, 1242, 1055.

Example 50 Trans-4-amidino-[(S)-N-[(S)-2-methoxycarbonylamino-3-isobutylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 451 in Table 1) hydrochloride

NMR (CDCl₃): 8.78 (br, 4H), 7.54 (t, 1H), 6.24 (d, 1H), 4.60 (d, 1H), 4.36 (d, 1H), 3.95 (m, 1H), 3.79 (m, 1H), 3.73 (s, 3H), 3.16 (m, 1H), 2.89 (m, 1H), 2.60 (m, 1H), 2.50-2.30 (m, 2H), 2.22 (m, 1H), 2.10-1.40 (m, 11H), 1.43 (s, 3H), 1.36 (s, 3H), 0.98 (d, 6H), 1.10-0.90 (m, 2H); IR: 3329, 3090, 2934, 2872, 1682, 1637, 1523, 1448, 1242, 1055.

Example 51 Trans-4-amidino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-ethylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 376 in Table 1) hydrochloride

NMR (CDCl₃): 8.81 (br, 2H), 8.72 (br, 2H), 7.58 (t, 1H), 6.05 (d, 1H), 4.61 (d, 1H), 4.38 (d, 1H), 4.23-4.05 (m, 2H), 3.94 (m, 1H), 3.77 (m, 1H), 3.13 (m, 1H), 2.99 (m, 1H), 3.70-3.50 (m, 3H), 2.19 (m, 1H), 2.10-1.40 (m, 10H), 1.44 (s, 3H), 1.37 (s, 3H), 1.28 (t, 3H), 1.22 (t, 3H), 1.10-0.90 (m, 2H); IR: 3323, 3076, 2932, 2870, 1685, 1637, 1521, 1444, 1242, 1059.

Example 52 Trans-4-amidino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-cyclopentylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 499 in Table 1) hydrochloride

NMR (CDCl₃): 8.84 (br, 2H), 8.71 (br, 2H), 7.54 (t, 1H), 6.01 (d, 1H), 4.61 (d, 1H), 4.34 (d, 1H), 4.25-4.10 (m, 2H), 3.96 (m, 1H), 3.74 (m, 1H), 3.25-3.00 (m, 2H), 2.91 (m, 1H), 2.59 (m, 1H), 2.21 (m, 1H), 2.20-1.40 (m, 18H), 1.47 (s, 3H), 1.37 (s, 3H), 1.29 (t, 3H), 1.10-0.90 (m, 2H); IR: 3312, 3070, 2937, 2868, 1689, 1637, 1521, 1446, 1242, 1055.

Example 53 Trans-4-amidino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-phenylmethylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 529 in Table 1) hydrochloride

NMR (CDCl₃): 8.83 (br, 2H), 8.69 (br, 2H), 7.49 (t, 1H), 7.38-7.20 (m, 5H), 5.97 (d, 1H), 4.60 (d, 1H), 4.21 (d, 1H), 4.20-4.15 (m, 2H), 3.83 (m, 1H), 3.78 (s, 2H), 3.62 (m, 1H), 3.11 (m, 1H), 2.88 (m, 1H), 2.54 (m, 1H), 2.18 (m, 1H), 2.15-1.40 (m, 10H), 1.47 (s, 3H), 1.37 (s, 3H), 1.28 (t, 3H) 1.10-0.90 (m, 2H); IR: 3315, 3062, 2932, 2866, 1685, 1639, 1518, 1446, 1240, 1055.

Example 54 Trans-4-amidino-[(S)-N-[(S)-2-propoxycarbonylamino-3-cyclopentylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 500 in Table 1) hydrochloride

NMR (CDCl₃): 8.79 (br, 2H), 8.70 (br, 2H), 7.55 (t, 1H), 6.03 (d, 1H), 4.60 (d, 1H), 4.36 (d, 1H), 4.20-3.92 (m, 3H), 3.75 (m, 1H), 3.20-2.80 (m, 3H), 2.62 (m, 1H), 2.20 (m, 1H), 2.10-1.40 (m, 20H), 1.46 (s, 3H), 1.38 (s, 3H), 0.94 (t, 3H), 1.10-0.90 (m, 2H); IR: 3283, 3080, 2935, 2870, 1685, 1647, 1521, 1446, 1238, 1060.

Example 55 Trans-4-amidino-[(S)-N-[(S)-2-propoxycarbonylamino-3-propylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 394 in Table 1) hydrochloride

NMR (CDCl₃): 8.78 (br, 2H), 8.69 (br, 2H), 7.57 (t, 1H), 6.05 (d, 1H), 4.59 (d, 1H), 4.36 (d, 1H), 4.09 (m, 1H), 4.05-3.90 (m, 2H), 3.79 (m, 1H), 3.11 (m, 1H), 2.92 (m, 1H), 2.62 (m, 1H), 2.60-2.45 (m, 2H), 2.19 (m, 1H), 2.10-1.40 (m, 14H), 1.43 (s, 3H), 1.37 (s, 3H), 0.99 (t, 3H), 0.94 (t, 3H), 1.10-0.90 (m, 2H); IR: 3314, 3084, 2937, 2874, 1689, 1637, 1523, 1444, 1238, 1062.

Example 56 Trans-4-amidino-[(S)-N-[(S)-2-propoxycarbonylamino-3-isobutylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 453 in Table 1) hydrochloride

NMR (CDCl₃): 8.74 (br, 4H), 7.58 (t, 1H), 6.06 (d, 1H), 4.58 (d, 1H), 4.38 (d, 1H), 4.18-3.90 (m, 3H), 3.78 (m, 1H), 3.08 (m, 1H), 2.97 (m, 1H), 2.63 (m, 1H), 2.50-2.30 (m, 2H), 2.20-1.40 (m, 14H), 1.42 (s, 3H), 1.37 (s, 3H), 0.98 (d, 6H), 0.94 (t, 3H), 1.10-0.90 (m, 2H) IR: 3335, 3086, 2926, 2874, 1685, 1637, 1521, 1448, 1242, 1062.

Example 57 Trans-4-amidino-[(S)-N-[(S)-2-propoxycarbonylamino-3-butylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 435 in Table 1) hydrochloride

NMR (CDCl₃): 8.78 (br, 2H), 8.68 (br, 2H), 7.53 (t, 1H), 6.05 (d, 1H), 4.59 (d, 1H), 4.08 (m, 1H), 4.05-3.90 (m, 2H), 3.77 (m, 1H), 3.13 (m, 1H), 2.92 (m (m, 1H), 2.50-2.45 (m, 2H), 2.20 (m, 1H), 2.10-1.40 (m, 16H), 1.43 (s, 3H), 1.37 (s, 3H), 0.94 (t, 3H), 0.91 (t, 3H), 1.10-0.90 (m, 2H); IR: 3269, 3067, 2932, 2863, 1685, 1635, 1521, 1446, 1238, 1062.

Example 58 Trans-4-amidino-[(S)-N-[(S)-2-propoxycarbonylamino-3-cyclohexyl-methylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 554 in Table 1) hydrochloride

NMR (CDCl₃): 8.83 (br, 2H), 8.65 (br, 2H), 7.49 (t, 1H), 6.01 (d, 1H), 4.58 (d, 1H), 4.34 (d, 1H), 4.20-3.95 (m, 3H), 3.78 (m, 1H), 3.13 (m, 1H), 2.92 (m, 1H), 2.61 (m, 1H), 2.50-2.30 (m, 2H), 2.29 (m, 1H), 2.02 (m, 2H), 1.95-1.10 (m, 21H), 1.42 (s, 3H), 1.36 (s, 3H), 0.95 (t, 3H), 1.10-0.90 (m, 2H); IR: 3346, 3088, 2926, 2852, 1693, 1655, 1543, 1523, 1448, 1238, 1062.

Example 59 Trans-4-amidino-[(S)-N-[(S)-2-propoxycarbonylamino-3-cyclobutylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 469 in Table 1) hydrochloride

NMR (CDCl₃): 8.78 (br, 2H), 8.71 (br, 2H), 7.56 (t, 1H), 6.03 (d, 1H), 4.60 (d, 1H), 4.33 (d, 1H), 4.20-3.90 (m, 3H), 3.77 (m, 1H), 3.55 (m, 1H), 3.12 (m, 1H), 2.94 (m, 1H), 2.62 (m, 1H), 2.40-2.25 (m, 2H), 2.20-1.40 (m, 17H), 1.40 (s, 3H), 1.33 (s, 3H), 0.94 (t, 1H), 1.10-0.90 (m, 2H); IR: 3296, 3072, 2932, 2874, 1685, 1639, 1521, 1444, 1240, 1060.

Example 60 Trans-4-amidino-[(S)-N-[(S)-2-propoxycarbonylamino-3-(1′-ethylpropylthio)-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 515 in Table 1) hydrochloride

NMR (CDCl₃): 8.81 (br, 2H), 8.75 (br, 2H), 7.52 (t, 1H), 5.99 (d, 1H), 4.60 (d, 1H), 4.27 (d, 1H), 4.20-3.95 (m, 3H), 3.70 (m, 1H), 3.13 (m, 1H), 2.90 (m, 1H), 2.70 -2.45 (m, 2H), 2.21 (m, 2H), 2.10-1.40 (m, 19H), 1.45 (s, 3H), 1.37 (s, 3H), 1.10-0.90 (m, 8H); IR: 3329, 3067, 2934, 2878, 1685, 1637, 1521, 1448, 1238, 1060.

Example 61 Trans-4-amidino-[(S)-N-[(S)-2-isobutyloxycarbonylamino-3-cyclopentyl-thio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 503 in Table 1) hydrochloride

NMR (CDCl₃): 8.82 (br, 2H), 8.64 (br, 2H), 7.54 (t, 1H), 6.03 (d, 1H), 4.59 (d, 1H), 4.37 (d, 1H), 4.05-3.90 (m, 2H), 3.90-3.70 (m, 2H), 3.15-3.05 (m, 2H), 2.92 (m, 1H), 2.62 (m, 1H), 2.23 (m, 1H), 2.10-1.40 (m, 19H), 1.47 (s, 3H), 1.38 (s, 3H), 0.94 (d, 6H), 1.10-0.90 (m, 2H); IR: 3279, 3082, 2961, 2872, 1685, 1643, 1518, 1446, 1238, 1053.

Example 62 Trans-4-amidino-[(S)-N-[(S)-2-isobutyloxycarbonylamino-3-isopropylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 413 in Table 1) hydrochloride

NMR (CDCl₃): 8.78 (br, 2H), 8.69 (br, 2H), 7.56 (t, 1H), 6.06 (d, 1H), 4.59 (d, 1H), 4.38 (d, 1H), 4.05-3.90 (m, 2H), 3.90-3.85 (m, 2H), 3.09 (m, 1H), 3.08-2.85 (m, 2H), 2.62 (m, 1H), 2.17 (m, 1H), 2.10-1.40 (m, 11H), 1.48 (s, 3H), 1.38 (s, 3H), 1.29 (dd, 6H), 0.93 (d, 6H), 1.10-0.90 (m, 2H); IR: 3271, 3069, 2934, 2876, 1685, 1641, 1518, 1448, 1238, 1053.

Example 63 Trans-4-amidino-[(S)-N-[(S)-2-propoxycarbonylamino-3-(3′-methylbutylthio)-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 572 in Table 1) hydrochloride

NMR (CDCl₃): 8.80 (br, 2H), 8.67 (br, 2H), 7.49 (t, 1H), 6.04 (d, 1H), 4.59 (d, 1H), 4.36 (d, 1H), 4.20-3.95 (m, 3H), 3.73 (m, 1H), 3.15 (m, 1H), 2.93 (m, 1H), 2.70-2.45 (m, 3H), 2.20 (m, 1H), 2.10-1.40 (m, 15H), 1.44 (s, 3H), 1.37 (s, 3H), 0.94 (t, 3H), 0.90 (d, 6H), 1.10-0.90 (m, 2H); IR: 3314, 3074, 2930, 2872, 1685, 1637, 1523, 1240, 1062.

Example 64 Trans-4-amidino-[(S)-N-[(S)-2-isobutyloxycarbonylamino-3-propylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 397 in Table 1) hydrochloride

NMR (CDCl₃): 8.77 (br, 2H), 8.68 (br, 2H), 7.56 (t, 1H), 6.07 (d, 1H), 4.58 (d, 1H), 4.39 (d, 1H), 4.05-3.90 (m, 2H), 3.90-3.70 (m, 2H), 3.10 (m, 1H), 2.95 (m, 1H), 2.65 (m, 1H), 2.60-2.40 (m, 2H), 2.18 (m, 1H), 2.10-1.40 (m, 13H), 1.43 (s, 3H), 1.37 (s, 3H), 0.99 (t, 3H), 0.94 (d, 6H), 1.10-0.90 (m, 2H); IR: 3314, 3069, 2935, 2874, 1685, 1637, 1521, 1448, 1240, 1053.

Example 65 Trans-4-amidino-[(S)-N-[(S)-2-isobutyloxycarbonylamino-3-isobutylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 456 in Table 1) hydrochloride

NMR (CDCl₃): 8.76 (br, 2H), 8.69 (br, 2H), 7.56 (t, 1H), 6.06 (d, 1H), 4.59 (d, 1H), 4.37 (d, 1H), 4.05-3.90 (m, 2H), 3.90-3.70 (m, 2H), 3.08 (m, 1H), 2.96 (m, 1H), 2.62 (m, 1H), 2.50-2.30 (m, 2H), 2.17 (m, 1H), 2.10-1.40 (m, 12H), 1.42 (s, 3H), 1.37 (s, 3H), 0.99 (d, 6H), 0.94 (d, 6H), 1.10-0.90 (m, 2H); IR: 3306, 3067, 2961, 2874, 1685, 1645, 1518, 1321, 1240, 1053.

Example 66 Trans-4-amidino-[(S)-N-[(S)-2-isobutyloxycarbonylamino-3-ethylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 380 in Table 1) hydrochloride

NMR (CDCl₃): 8.74 (br, 2H), 8.70 (br, 2H), 7.58 (t, 1H), 6.08 (d, 1H), 4.58 (d, 1H), 4.41 (d, 1H), 4.05-3.90 (m, 2H), 3.90-3.70 (m, 2H), 3.07 (m, 1H), 2.97 (m, 1H), 2.75-2.50 (m, 3H), 2.20-1.40 (m, 12H), 1.43 (s, 3H), 1.37 (s, 3H), 1.21 (t, 3H), 0.93 (d, 6H), 1.10-0.90 (m, 2H); IR: 3279, 3076, 2934, 2874, 1695, 1637, 1521, 1446, 1240, 1055.

Example 67 Trans-4-amidino-[(S)-N-[(S)-2-butoxycarbonylamino-3-isobutylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 455 in Table 1) hydrochloride

NMR (CDCl₃): 8.78 (br, 2H), 8.66 (br, 2H), 7.55 (br, 1H), 5.97 (d, 1H), 4.57 (d, 1H), 4.38 (d, 1H), 4.14 (m, 1H), 3.99 (m, 1H), 3.80 (m, 1H), 3.07 (m, 1H), 2.99 (m, 1H) 2.64 (m, 1H), 2.39 (m, 2H), 2.22 (m, 1H), 2.18-1.74 (m, 8H), 1.62 (m, 4H), 1.50-1.33 (m, 2H), 1.42 (s, 3H), 1.37 (s, 3H), 1.08-0.95 (m, 2H), 0.98 (d, 6H), 0.93 (t, 3H); IR: 3316, 3084, 2959, 2932, 1686, 1638, 1522, 1449, 1242, 1065.

Example 68 Trans-4-amidino-[(S)-N-[(S)-2-butoxycarbonylamino-3-butylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 437 in Table 1) hydrochloride

NMR (CDCl₃): 8.72 (br, 4H), 7.57 (br, 1H), 5.99 (d, 1H), 4.56 (d, 1H), 4.40 (d, 1H), 4.12 (m, 1H), 3.97 (m, 2H), 3.73 (m, 1H), 3.02 (m, 2H), 2.68-2.44 (m, 4H), 2.51 (m, 1H), 2.22 (m, 1H), 2.08-1.70 (m, 8H), 1.64-1.59 (m, 3H), 1.54-1.49 (m, 3H), 1.44-1.34 (m, 2H), 1.41 (s, 3H), 1.37 (s, 3H), 1.10-0.96 (m, 2H), 0.93 (t, 3H), 0.91 (t, 3H); IR: 3299, 3084, 2959, 2932, 1686, 1638, 1520, 1449, 1242, 1065.

Example 69 Trans-4-amidino-[(S)-N-[(S)-2-butoxycarbonylamino-3-isopropylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 412 in Table 1) hydrochloride

NMR (CDCl₃): 8.76 (br, 2H), 8.69 (br, 2H), 7.57 (br, 1H), 5.97 (d, 1H), 4.58 (d, 1H), 4.38 (d, 1H), 4.13 (m, 1H), 3.98 (m, 2H), 3.78 (m, 1H), 3.10-3.00 (m, 2H), 2.99 (m, 1H), 2.64 (m, 1H), 2.35-2.00 (m, 7H), 2.00-1.90 (m, 4H), 1.62 (m, 4H), 1.47 (s, 3H), 1.38 (s, 3H), 1.31 (d, 3H), 1.26 (d, 3H), 1.10-1.00 (m, 2H), 0.93 (t, 3H); IR: 3328, 3079, 2961, 2932, 1686, 1644, 1518, 1449, 1242, 1065.

Example 70 Trans-4-amidino-[(S)-N-[(S)-2-butoxycarbonylamino-3-propylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 396 in Table 1) hydrochloride

NMR (CDCl₃): 8.76 (br, 2H), 8.67 (br, 2H), 7.56 (br, 1H), 5.98 (d, 1H), 4.56 (d, 1H), 4.39 (d, 1H), 4.13 (m, IH), 3.98 (m, 2H), 3.80 (m, 1H), 3.00 (m, 2H), 2.61 (m, 1H), 2.50 (m, 2H), 2.30-1.78 (m, 10H), 1.55 (m, 5H), 1.42 (s, 3H), 1.41-1.32 (m, 2H), 1.37 (s, 3H), 1.04-0.88 (m, 2H), 0.99 (t, 3H), 0.93 (t, 3H); IR: 3318, 3084, 2963, 2934, 1686, 1642, 1518, 1449, 1242, 1065.

Example 71 Trans-4-amidino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-cyclopentylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 501 in Table 1) hydrochloride

NMR (CDCl₃): 8.77 (br, 2H), 8.64 (br, 2H), 7.59 (br, 1H), 5.80 (d, 1H), 4.84 (m, 1H), 4.57 (d, 1H), 4.38 (d, 1H), 3.96 (m, 1H), 3.78 (m, 1H), 3.06 (m, 1H), 3.01 (m, 1H), 2.62 (m, 1H), 1H), 2.19 (m, 2H), 2.03 (m, 9H), 1.83 (m, 2H), 1.66 (m, 2H), 1.66 (m, 2H), 1.55 (m, 4H), 1.45 (s, 3H), 1.37 (s, 3H), 1.25 (d, 6H), 1.00 (m, 2H); IR: 3329, 3086, 2936, 1686, 1638, 1510, 1149, 1244, 1111.

Example 72 Trans-4-amidino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-isobutylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 454 in Table 1) hydrochloride

NMR (CDCl₃): 8.78 (br, 2H), 8.63 (br, 2H), 7.59 (br, 1H), 5.80 (d, 1H), 4.84 (m, 1H), 4.57 (d, 1H), 4.37 (d, 1H), 3.95 (m, 1H), 3.79 (m, 1H), 3.02 (m, 2H), 2.62 (m, 1H), 2.40 (m, 2H), 2.26-1.92 (m, 8H), 1.90-1.78 (m, 4H), 1.41 (s, 3H), 1.36 (s, 3H), 1.25 (d, 6H), 1.10-1.00 (m, 2H), 0.98 (d, 6H); IR: 3318, 2961, 2932, 1686, 1642, 1514, 1244, 1111.

Example 73 Trans-4-amidino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-butylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 436 in Table 1) hydrochloride

NMR (CDCl₃): 8.78 (br, 2H), 8.61 (br, 2H), 7.58 (br, 1H), 5.80 (d, 1H), 4.83 (m, 1H), 4.56 (d, 1H), 4.38 (d, 1H), 3.95 (m, 1H), 3.77 (m, 1H), 3.02 (m, 12H), 2.70-2.44 (m, 3H), 2.24 (m, 1H), 2.16-1.80 (m, 7H), 1.72 (m, 2H), 1.52 (m, 3H), 1.41 (s, 3H), 1.39 (m, 2H), 1.36 (s, 3H), 1.25 (d, 3H), 1.08 (m, 2H), 0.91 (t, 3H); IR: 3314, 2961, 2932, 1684, 1640, 1516, 1447, 1252, 1111.

Example 74 Trans-4-amidino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-propylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 395 in Table 1) hydrochloride

NMR (CDCl₃): 8.88 (br, 2H), 8.54 (br, 2H), 7.55 (br, 1H), 5.80 (d, 1H), 4.84 (m, 1H), 4.55 (d, 1H), 4.38 (d, 1H), 3.93 (m, 1H), 3.78 (m, 1H), 3.00 (m, 2H), 2.64-2.42 (m, 3H), 2.30-1.86 (m, 9H), 1.55 (m, 4H), 1.41 (s, 3H), 1.37 (s, 3H), 1.26 (d, 3H), 1.24 (d, 3H), 1.00-0.90 (m, 2H), 0.99 (t, 3H); IR: 3329, 2973, 2932, 1686, 1638, 1522, 1449, 1246, 1111.

Example 75 Trans-4-amidino-[(S)-N-[(S)-2-isopropoxycarbonylamino-3-phenylmethylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 531 in Table 1) hydrochloride

NMR (CDCl₃): 8.75 (br, 2H), 8.63 (br, 2H), 7.56 (br, 1H), 7.33-7.22 (m, 5H), 5.81 (d, 1H), 4.82 (m, 1H), 4.56 (d, 1H), 4.31 (d, 1H), 3.82-3.60 (m, 2H), 3.78 (s, 1H), 3.77 (s, 1H), 2.99 (m, 2H), 2.80 (m, 1H), 2.18 (m, 1H), 2.07-1.76 (m, 7H), 1.66 (m, 2H), 1.45 (s, 3H), 1.38 (s, 3H), 1.26 (d, 3H), 1.24 (d, 3H), 0.98 (m, 2H); IR: 3329, 3084, 2980, 2932, 1686, 1647, 1508, 1451, 1242, 1111.

Example 76 Trans-4-amidino-[(S)-N-[(S)-2-butoxycarbonylamino-3-phenylmethylthio-3-methylbutanoyl]prolyl]aminomethylcyclohexane (Compound No. 532 in Table 1) hydrochloride

NMR (CDCl₃): 8.76 (br, 2H), 8.65 (br, 2H), 7.53 (br, 1H), 7.33-7.21 (m, 5H), 5.97 (d, 1H), 4.57 (d, 1H), 4.31 (d, 1H), 4.11 (m, 1H), 4.01 (m, 1H), 3.86-3.76 (m, 1H), 3.78 (s, 1H), 3.77 (s, 1H), 3.65 (m, 1H), 3.06 (m, 1H), 2.95 (m, 1H), 2.56 (m, 1H), 2.24-1.76 (m, 10H), 1.62 (m, 3H), 1.46 (s, 3H), 1.42-1.35 (m, 2H), 1.39 (s, 3H), 1.04-0.91 (m, 2H), 0.93 (t, 3H); IR: 3337, 3086, 2961, 2934, 1686, 1638, 1522, 1451, 1242, 713.

Test Example 1 Measurement of Thrombin Activity

i) Method for Measuring Inhibition of Hydrolysis of Synthesized Substrate (S-2238)

S-2238 (Kabi) was dissolved in Tris/HCl buffer (pH 8.3) to prepare a solution of S-2238at a concentration of 80 μM in 0.4 M Tris/HCl. To 175 μl of this solution was added 515 μl of an aqueous solution of the compound of the present invention and the mixture was incubated at 37° C. for one minute, and then the mixture was mixed with 10 μl of a 4.4 unit/ml solution of bovine thrombin (Mochida). The rate of hydrolysis reaction of the substrate was determined by detecting alteration of absorbance at 405 nm at 37° C. The concentration of the inhibitor (the compound of the present invention) which gave half of the absorbance value of a sample without the inhibitor was determined as I₅₀ (μM).

ii) Method for Measuring Inhibition of Rat Plasma Coagulation

The compound of the present invention was dissolved in water or physiological saline in a total volume of 0.1 ml, and then the solution was mixed with 0.1 ml of rat plasma and the mixture was incubated at 37° C. for 30 seconds. The reaction mixture was mixed with 0.1 ml of 8 unit/ml solution of bovine thrombin (Mochida) was, and the coagulation time was measured at 37° C. The concentration of the inhibitor (the compound of the present invention) which doubled the coagulation time of a sample without the inhibitor was determined as I₅₀ (μM).

iii) Method for Measuring Antithrombotic Activity in Rat Plasma after Oral Administration

The compound of the present invention in the amount of 30 mg/kg was orally administered as an aqueous solution or a suspension to rats starved overnight using an oral tube.

After one hour and three hours, 2 ml of blood was collected from abdominal large vein, and antithrombotic activity in plasma was measured by the method described in the above ii). The values were compared with the result obtained by using blood of a rat not administered with the inhibitor (the compound of the present invention), and prolonging effects on coagulation time were indicated as relative values representing rates of prolongation of thrombin time based on a control as being 1.

Test Example 2 Measurement of Antitrypsin Activity

i) Method for Measuring Inhibition of Hydrolysis of Synthesized Substrate (S-2222)

S-2222 (Kabi) was dissolved in Tris/HCl buffer (pH 8.3) to prepare a solution of S-2222 at a concentration of 400 μM in 0.4 M Tris/HCl. To 175 μl of this solution was added 515 μl of an aqueous solution of the compound of the present invention and the mixture was incubated at 37° C. for one minute. The reaction mixture was then mixed with 10 μl of 1 or 2 mg/ml solution of bovine trypsin (Sigma). The rate of hydrolysis reaction of the substrate was determined by detecting alteration of absorbance at 405 nm at 37° C. The concentration of the an inhibitor (the compound of the present invention) which gave the half of the absorbance value of a sample without the inhibitor was determined as I₅₀ (μM).

The results obtained by the aforementioned Test Examples 1 and 2 are shown in the Table 2 below.

TABLE 2 Antithrombin activity Thrombin time I₅₀ (μM) prolongation Synthesized Rat Antitrypsin ratio upon oral Example substrate plasma activity administration No. method method I₅₀ (μM) 1 hour 3 hours  1 0.045 0.044 41 2.16 10.36  2 0.051 0.057 48 1.46 10.31  3 0.091 0.068 38 3.19 2.80  4 0.070 0.048 52 1.84 3.72  5 0.14 0.11 33  6 0.080 0.082 32  7 0.13 27  8 0.024 7.5  9 0.29 68 10 0.10 32 2.89 11 0.097 31 1.67 12 0.081 37 5.98 13 0.076 23 6.13 14 0.079 22 2.79 15 0.36 126 1.29 16 0.069 21 5.92 17 0.089 29 4.02 18 0.11 33 4.09 19 0.14 38 3.91 20 0.57 71 1.36 21 0.11 22 5.46 22 0.068 15 4.13 23 0.48 134 1.36 24 0.095 27 6.07 25 0.14 41 3.26 26 0.12 35 3.10 27 0.086 34 2.32 28 0.081 25 2.19 29 0.070 31 3.40 30 0.22 62 2.56 31 0.078 24 5.21 32 0.10 28 2.92 33 0.093 30 4.77 34 0.074 0.068 29 2.35 7.22 35 0.11 31 3.76 36 0.074 30 4.11 37 0.16 34 3.21 38 0.10 24 4.41 39 0.084 32 4.90 40 0.054 6.4 41 0.073 6.6 42 6.8 43 0.092 7.4 44 0.076 12 45 0.072 46 0.072 47 0.14 6.8 48 0.11 8.5 49 0.14 4.2 50 0.13 6.6

Industrial Applicability

The penicillaminamide derivatives of the present invention and salts thereof have potent inhibitory activity against thrombin and excellent oral absorbability. Therefore, they are useful as orally available antithrombotic agents, i.e., anticogulants. 

What is claimed is:
 1. A compound represented by the following general formula (I) or a salt thereof, or a hydrate thereof or a salt thereof, or a hydrate thereof or a solvate thereof:

wherein: n represents 1 or 2; R¹ represents a C₁-C₁₀ alkyl group which may be substituted with a C₃-C₁₀ cycloalkyl group or carboxyl group, a C₆-C₁₀ aryl group which may be substituted, a C₃-C₁₀ cycloalkyl group which may be substituted, or C₇-C₁₂ aralkyl group which may be substituted; R² represents hydrogen atom, a C₁-C₁₀ alkyl group, a C₇-C₁₂ aralkyl group which may be substituted, —COR⁴ (wherein R⁴ represents hydrogen atom, a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group, an C₆-C₁₀ aryl group which may be substituted, a C₆-C₁₀ aryloxy group which may be substituted, a C₃-C₁₀ cycloalkyl group which may be substituted, a C₃-C₁₀ cycloalkyloxy group which may be substituted, a C₇-C₁₂ aralkyl group which may be substituted, or a C₇-C₁₂ aralkyloxy group), or —SO₂R⁵ (where R⁵ represents a C₁-C₁₀ alkyl group, a C₆-C₁₀ aryl group which may be substituted, a C₃-C₁₀ cycloalkyl group which may be substituted, or a C₇-C₁₂ aralkyl group which may be substituted), and R³ represents amino group or amidino group, provided that the following compounds: the compound wherein R¹ represents methyl group, R² represents ethoxycarbonyl group, R³ represents amino group, and n represents 1; the compound wherein R¹ represents methyl group, R² represents methylsulfonyl group, R³ represents amino group, and n represents 1; the compound wherein R¹ represents ethyl group, R² represents methylsulfonyl group, R³represents amino group, and n represents 1; and the compound wherein R¹ represents isopropyl group, R² represents ethoxycarbonyl group, R³ represents amidino group, and n represents 1 are excluded.
 2. The compound or the salt thereof, or the hydrate thereof or the solvate thereof according to claim 1, wherein at least one of the groups which may be substituted comprises a substituent selected from the group consisting of a C₁C₆ alkyl group, a C₁-C₆ haloalkyl group, a C₁-C₆ alkoxy group, hydroxyl group, carboxyl group, a C₂-C₇ carboxyalkyl group, a C₂-C₇ carboxyalkyloxy group, a C₂-C₇ acyloxy group, a C₂-C₇ alkoxycarbonyl group, a C₂-C₇ alkoxycarbonyloxy group, a C₈-C₁₀ aralkyloxycarbonyl group, a C₇-C₉ alkoxycarbonylalkoxy group, and a halogen atom.
 3. The compound or the salt thereof, or the hydrate thereof or the solvate thereof according to claim 1, wherein R¹ represents a C₄-C₁₀ alkyl group, a C₆-C₁₀ aryl group which may be substituted, a C₃-C₁₀ cycloalkyl group which may be substituted, or a C₇-C₁₂ aralkyl group which may be substituted, and R³ represents amidino group.
 4. The compound or the salt thereof, or the hydrate thereof or the solvate thereof according to claim 1, wherein R³ represents amino group.
 5. The compound or the salt thereof, or the hydrate thereof or the solvate thereof according to claim 1, wherein R² represents hydrogen atom, a C₁-C₁₀ alkyl group, a C₇-C₁₂ aralkyl group which may be substituted, or —COR⁴ wherein R⁴ is the same as that defined above.
 6. The compound or the salt thereof, or the hydrate thereof or the solvate thereof according to claim 1, wherein R² represents —COR⁴ wherein R⁴ represents a C₁₀ alkyl group, a C₁-C₁₀ alkoxy group, a C₆-C₁₀ aryl group which may be substituted, a C₆-C₁₀ aryloxy group which may be substituted, a C₃-C₁₀ cycloalkyl group which may be substituted, a C₃-C₁₀ cycloalkyloxy group which may be substituted, a C₇-C₁₂ aralkyl group which may be substituted, or a C₇-C₁₂ aralkyloxy group which may be substituted.
 7. Trans-4-amino-[(S)-N—[(S)-2-propoxycarbonylamino-3-isopropylthio-3-methyl-butanoyl]prolyl]aminomethylcyclohexane or a salt thereof, or a hydrate thereof. or a solvate thereof.
 8. Trans-4- amino-[(S)-N-[(S)-2-ethoxycarbonylamino-3-isopropylthio-3-methyl-butanoyl]prolyl]aminomethylcyclohexane or a salt thereof, or a hydrate thereof or a solvate thereof.
 9. A pharmaceutical composition comprising a substance selected from the group consisting of the compound and the salt thereof, and the hydrate thereof and the solvate thereof according to claim 1 together with a pharmaceutically acceptable additive.
 10. A method for manufacturing a pharmaceutical composition, comprising: combining at least one of the compound, salt thereof, hydrate thereof, and solvate thereof of claim 1, with a pharmaceutically acceptable additive.
 11. A method for inhibiting proteases, comprising: administering a therapeutically effective amount of at least one of the compound, salt thereof, hydrate thereof, and solvate thereof of claim
 1. 12. A method of inhibiting coagulation, comprising: administering a therapeutically effective amount of the pharmaceutical composition of claim
 9. 